What is ADD? A neurobehavioral disorder that begins in early childhood and can continue into adulthood ADHD may be associated with long-term adverse outcomes: • Deficits.
Download ReportTranscript What is ADD? A neurobehavioral disorder that begins in early childhood and can continue into adulthood ADHD may be associated with long-term adverse outcomes: • Deficits.
Slide 1
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 2
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 3
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 4
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 5
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 6
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 7
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 8
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 9
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 10
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 11
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 12
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 13
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 14
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 15
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 16
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 17
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 18
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 19
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 20
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 21
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 22
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 23
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 24
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 25
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 26
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 27
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 28
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 29
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 30
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 31
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 32
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 33
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 34
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 35
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 36
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 37
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 38
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 39
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 40
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 41
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 42
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 43
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 44
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 45
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 46
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 47
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 48
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 49
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 50
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 51
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 52
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 53
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 54
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 55
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 56
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 57
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 58
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 59
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 60
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 61
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 62
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 63
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 64
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 65
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 66
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 67
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 68
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 69
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 70
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 71
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 72
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 73
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 74
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 75
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 76
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 77
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 78
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 79
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 80
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 81
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 82
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 83
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 84
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 85
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 86
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 87
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 88
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 89
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 90
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 91
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 92
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 93
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 94
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 95
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 96
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 97
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 98
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 99
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 100
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 101
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 102
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 103
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 104
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 105
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 106
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 107
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 108
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 109
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 110
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 111
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 112
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 113
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 114
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 115
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 2
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 3
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 4
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 5
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 6
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 7
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 8
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 9
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 10
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 11
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 12
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 13
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 14
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 15
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 16
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 17
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 18
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 19
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 20
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 21
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 22
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 23
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 24
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 25
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 26
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 27
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 28
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 29
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 30
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 31
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 32
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 33
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 34
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 35
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 36
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 37
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 38
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 39
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 40
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 41
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 42
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 43
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 44
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 45
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 46
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 47
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 48
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 49
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 50
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 51
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 52
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 53
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 54
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 55
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 56
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 57
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 58
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 59
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 60
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 61
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 62
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 63
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 64
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 65
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 66
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 67
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 68
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 69
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 70
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 71
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 72
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 73
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 74
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 75
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 76
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 77
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 78
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 79
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 80
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 81
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 82
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 83
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 84
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 85
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 86
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 87
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 88
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 89
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 90
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 91
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 92
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 93
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 94
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 95
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 96
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 97
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 98
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 99
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 100
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 101
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 102
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 103
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 104
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 105
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 106
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 107
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 108
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 109
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 110
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 111
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 112
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 113
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 114
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague
Slide 115
What is ADD?
A neurobehavioral disorder that begins in
early childhood and can continue into
adulthood
ADHD may be associated with long-term
adverse outcomes:
• Deficits in academic skills
• Deficits in family/social skills
• Learning disabilities
May be accompanied by internalizing
disorders (sadness, anxiety) as well as
aggressive and oppositional disorders and
learning disabilities
ADHD
Attention deficit hyperactivity disorder as a
diagnosis generates controversy.
It is both under & over diagnosed-some
believe it does not exist.
Epidemiological studies show 5-10% of
school age children may be classified with the
disorder.
It is a complex neuro-developmental
constellation of problems rather than a single
disorder.
Often associated with co-morbid conditions.
No diagnostic test to confirm clinical
Historical background
1897 Kerr- Word blindness in smart
children
1937 Bradley- Benzedrine & Brain
activity
1941 Bender -Minimal Brain &
Hyperkinesis
1947 Strauss-Brain damaged child
syndrome
1963 Connors/EisenbergRitalin&Hyperkinesis
1968 DSM II Hyperactivity
Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In
summary, the diagnostic criteria for ADHD include:
EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and
are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily
distracted," "loses...toys, school assignments")
OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about
or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out
answers," "difficulty waiting turn," "interrupts or intrudes on others") that have
persisted for 6 months and are maladaptive
In addition, the symptoms needed to have been present before age 7, be expressed in
at least two settings (DSM-III and DSM-IV mention work here), and demonstrate
clear evidence of impairment.
ADHD
Legal Status
Americans with Disabilities Act
(ADA)
Rehabilitation Act of 1973
ADHD Epidemiology
Most commonly diagnosed neurobehavioral
disorder in children1, 2
Symptoms typically appear between the ages
of 3 and 7
5%-10% of school-aged children may have
ADHD; may bigher
Boys are diagnosed 4 to 9 times more often
than girls4
In up to 60% of children, symptoms of ADHD
continue into adulthood5-7
ADHD
Genetic Studies
Strong familial association with increase
first degree relatives
Monozygotic twin studies show 60-90%
concordance rate Adoption/Consanguinity -positive
correlation
Specific Genes
Polygenetic disorder involving multiple
genes
Dopamine transporter
gene DAT 1
Dopamine receptor D4/Chromosome 3 ,5
ADHD
Laboratory Test
No specific blood test
However
Lead level, CBC, EKG, Liver
function may be indicated in
certain cases.
Blood level of certain medication
required
Toxicology screen in suspected
cases of drug use
EEG indicated for seizure
Recent Findings
Low birth weight, Fetal Alcohol syndrome
Smoking during pregnancy +
Alcohol,cocaine
Higher rates injury medical bills.
Untreated leads to sociopathy -increase
driving offenses, delinquency, school&
work failure_
Increased smoking & substance abuse
Multimodal Treatment study (MTA) 2001
Closely monitored med. management
more beneficial than intensive behavioral
treatment
Girls
ADHD
Girls show less hyperactivity than
boys
Often Overwhelmed, disorganized &
scattered
Depression often coexists with ADHD
Less potential for antisocial personality
& substance abuse
Tend to have higher rate of adolescent
pregnancy and substance abuse
compared to other females.
Similar neuro- anatomical substrate
•Adolescents face increasing demands for planning,
organizing, self control, and time management, thus
requiring increased executive function. What appeared
as hyperactivity in the younger child emerges as
restlessness
• In the adolescent. Poor organizational skills make high
school and college years difficult for the adolescent and
young adult with ADHD. Impairment follows and
manifests as lower grades, more school suspensions,
and higher college drop-out rates.
•Furthermore, higher rates of illegal substance and
alcohol use in adults with ADHD appear to have their
beginnings in the adolescent years.
TESTING
Tri –State AFF Rating Scale.
Psychological Testing
Wechsler Intelligence Scale for Children
(WISC-III)
Wechsler Intelligence Scale for
Children(WISC-R)
Woodcock-Johnson Reading Mastery Test
Peabody Individual Achievement Test
Peabody Picture Vocabulary Test
Vineland Adaptive Behavior Scales
Thematic Apperception Test (TAT).
Connors’ Parent &Teacher Rating Scale.
•For children with ADHD, academic difficulties are common.
Among children with ADHD, prevalence of learning disabilities has
not been well determined, with a wide range of reported levels
from 9% to 94%.
• It is clear, that adults with ADHD have adaptive impairments
relating to schooling in general. However, whether or not true
learning disabilities remain an issue for adults with ADHD has not
been determined. Conduct (20%) and oppositional-defiant (40%)
disorders are commonly identified among children with ADHD.
•
•The prevalence of the disruptive behavior disorders decreases
significantly beginning in adolescence and extending into
adulthood; however, in adulthood, antisocial disorder is one of the
comorbidities that can persist independently of continued ADHD
symptoms.
DSM-V® Defines 3 ADHD
Subtypes
3 categories of ADHD (DSM-IV®
criteria)1
• Predominantly inattentive type
• Predominantly hyperactive-impulsive
type
• Combined type
1APA.
DSM-IV. 1994.
Meeting the Diagnostic Criteria
for ADHD
Presence of 6 or more symptoms of
inattention or hyperactivity/impulsivity
that have persisted for at least 6 months
to a degree that is maladaptive and
inconsistent with developmental level
• Symptoms present before age 7 years
• Impairment from symptoms present in 2 or
more settings
• Significant social, academic, or occupational
impairment
• Exclude other mental disorders
APA. DSM-IV. 1994.
DSM IV-R criteria for diagnosis
6 symptoms of inattention for>6months
Fails to give close attention to
details/makes careless mistakes in
schoolwork/activities.
Does not listen when spoken to directly.
Does not follow through on instructions
and fails to finish schoolwork,chores
other duties.
Difficulties organizing tasks and activities.
Avoids and dislikes to engage in tasks
that require sustained mental effort
ADD
Difficulties sustaining attention in
tasks or play activities.
Often loses things necessary for
tasks or activities- toys,books,
pencils, assignments.
Easily distracted by extraneous
stimuli.
Often forgetful in daily activities.
Daydreams in situations of stress
ADHD
Impulsive
Often blurts out answers before
questions have been completed
Often has difficulty waiting turn
Often interrupts or intrudes on
others- in conversations and
games.
Changes goals and other interests
suddenly
ADHD
Symptoms that caused impairment
were present before age of
7years
Symptoms present in two or
more settings
Clear clinical evidence of
significant impairment in social
academic or occupational
functioning
Symptoms do not occur exclusively
Psychiatric comorbidity
Depression
Bipolar Affective Disorder
Conduct disorder
Oppositional Defiant disorder
Generalized Anxiety Disorder
OCD
Substance use & abuse
Hallucinations-/childhood schizophrenia
MR
Neurological Substrate
•The earliest indication of abnormal brain activity with
ADHD came from electrophysiological studies, which
demonstrated that children with ADHD exhibited lower
amplitudes in brain areas believed to be correlated with
attention and memory.
•In recent years, various imaging modalities have
contributed both to confirming the validity of ADHD in
adults and to better understanding the disorder. Magnetic
resonance imaging (MRI) studies provide data showing
that the prefrontal lobe and right caudate nucleus is smaller
in patients with ADHD.
•In adults with ADHD since childhood, positron emission
tomography (PET) scans have revealed decreased frontal
cortical activity as well as abnormal regional and global
glucose metabolism during the performance of a task
involving executive function.
•Additionally, PET scans actually have been able to demonstrate
decreased dopamine neurotransmission in the left and medial
portions of the prefrontal cortex. These findings are significant
because the stimulant pharmacologic agents used to ameliorate
ADHD symptoms are known to increase extracellular
catecholamines.
• Functional magnetic resonance imaging (fMRI), a technique that
maps neuronal activity within the brain by using the naturally
occurring changes in blood oxygen levels that follow any neural
activity, is just beginning to be applied to ADHD research.
Preliminary investigations using fMRIs have been a pioneering
modality in determining the etiology and pathophysiology of
ADHD.
• FMRI comparison of adults with ADHD vs normal controls during
a Stroop interference task demonstrated failure of the anterior
cingulate gyrus to activate in the ADHD subjects, suggesting that
these individuals were depending on a different part of the brain to
accomplish this task.
Dopamine Pathways in ADD
Dopamine Pathways in ADD
EEG and ADD
Cortical abnormalities in children
with ADHD
Results of structural brain imaging studies of
patients with attention-deficit hyperactivity
disorder have shown subtle reductions in total
brain volume and in volumes of the right frontal
lobe and caudate nucleus.
Although various conventional volumetric and
voxel-based methods of image analysis have
been used in these studies, regional brain size
and grey-matter abnormalities have not yet been
mapped over the entire cortical surface in
patients with this disorder.
The task of mapping these features in patients
with attention-deficit hyperactivity disorder
continues to improve.
Abnormal morphology was noted in the
frontal cortices of patients with attentiondeficit hyperactivity disorder, with reduced
regional brain size localised mainly to
inferior portions of dorsal prefrontal
cortices bilaterally.
Brain size was also reduced in anterior
temporal cortices bilaterally.
Prominent increases in grey matter were
recorded in large portions of the posterior
temporal and inferior parietal cortices
bilaterally.
The frontal, temporal, and parietal regions
are heteromodal association cortices that
constitute a distributed neural system,
which subserves attention and behavioural
inhibition.
Physicians have identified region-specific
anatomical abnormalities in cortical
components of attentional systems, which
may help better account for the symptoms
of attention-deficit hyperactivity disorder.
Volume 362, Number 9397 Lancet / Sowell
•Our morphometric procedures allow more precise
localization of group differences than do the methods
used in previous studies," lead author Elizabeth R.
Sowell, PhD, from the University of California at Los
Angeles, says in a news release.
• "Our results therefore suggest that the disturbances
in prefrontal cortices are localized to more inferior
aspects of prefrontal regions than was previously
appreciated.
•Our findings also indicate that prefrontal
abnormalities are represented bilaterally, by contrast
to the predominantly right-sided findings that were
emphasized in other reports."
•The findings are not only in brain regions
controlling attention, but also in regions that
subserve impulse control," says coauthor
Bradley Peterson, MD, from Columbia
University and the New York State Psychiatric
Institute in New York City.
• "Disordered impulse control is often the most
clinically debilitating symptom in children with
ADHD."
•Although measures of the severity of ADHD
symptom subtypes generally did not correlate
significantly with these morphological
measures, gray matter in the occipital lobe was
inversely correlated with measures of
inattention.
FMRI and ADD 8 yrs vs 28 yrs
•Pharmacotherapy is the first line of treatment for ADHD. Studies
of the treatment of ADHD in childhood show that pharmacological
treatment is superior to behavioral treatment and that combining
the 2 treatments does not significantly improve ADHD symptoms[,
although it may provide added benefit in the event of a comorbid
anxiety disorder or oppositional disorder.
• Until the launch of atomoxetine, stimulant medications were the
only medications to receive FDA approval for treatment of ADHD.
Atomoxetine is the only medication with FDA approval for
management of ADHD in adults.
•Antidepressants (for all ages) and antihypertensives (in children)
are used to treat ADHD that is refractory to treatment with
stimulants.
•For children and adolescents, a review of therapeutic trials
shows a clear pattern of symptom improvement with
stimulants, with approximately 70% of patients responding to
treatment.
• Once dosage was adequately titrated for adults, studies
showed similar patterns of symptom improvement. ADHD is
presumed to stem from dysfunction of the catecholamine
system, particularly dopamine and norepinephrine.
• Stimulants enhance transmission of catecholamines, often
by blocking dopamine and norepinephrine reuptake
transporters, with the net effect of increasing attention and
decreasing impulsivity.
Pharmacotherapy Overview
Understanding Dopamine
Neurotransmission in ADHD
Synaptic terminal
Vesicles containing DA
DA transporters
3. Dopamine in the synapse is
reabsorbed (reuptake)
1. Dopamine is
released into the
synapse
2. Dopamine temporarily
attaches to receptors
Postsynaptic cell
Adapted from: Barkley RA. Sci Am. 1998;279:66-71.
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.
Barkley RA. Sci Am. 1998;279:66–71.
Dougherty DD et al. Lancet. 1999;354:2132–2133.
DA receptors
Dopamine Pathways in ADD
Pharmacotherapy
Studies including randomized trials have
established the efficiency of stimulant
medication for alleviating symptoms.
Clear indication that medication is more
effective than psychosocial therapies.
Effect central norepinephrine/dopamine
overcoming deficits in inhibitory control and
working memory.
Pharmacotherapy
Effects rapid & appear within 30 minutes
Short half- life fast absorption,metabolism and
elimination
Peak 1-3 hours- eliminated by 5 hours
Sustain release can last up to 9 hours
Short term effects well studied need more
long term studies
One most extensive Klein MD /Mannuzza
Studied effects on 226 kids over 16 yrs-no
long term adverse outcomes( incl..Growth)
Stimulant Medication /Dosage Form(s) Available
Methylphenidate
Ritalin 5mg,10mg, and 20mg tablets / Ritalin SR
Focalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg
Methylphenidate extended release
Ritalin LA 20mg,30mg,40mg capsules
Metadate CD 10mg and 20-mg capsules /Metadate ER
Concerta 18mg, 27mg, 36mg, and 54-mg caplets
Methylin / Methylin ER
Dextroamphetamine sulfate /amphetamine sulfate mix
Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabs
Adderall XR 5mg,10mg,15mg,20mg,30mgcapsules
Dextroamphetamine
Dexedrine 5mg, 10mg, and 15mg sustained release caps
Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixir
Dextrostat spansules 5mg 10mg
Methamphetamine
Desoxyn 5mg tabs
Pemoline ( Cylert)
18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable
•November 2002, atomoxetine (Strattera) was the first
medication approved by the Food and Drug Administration (FDA)
for the treatment of ADHD, not just for children and adolescents,
but specifically for adults as well
• This is the first medication to receive an FDA indication for
treatment of ADHD in adults, and in fact the initial clinical trials
were done in adults rather than children.
• Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that lacks cardiovascular toxicity.
•Atomoxetine does not have abuse potential, minimizing the
likelihood that it would be sold as a street drug. Therefore, unlike
the stimulants,It is not classified as a controlled substance and
does not require a special prescription.
•Atomoxetine has been shown to alleviate both inattentive and
hyperactive symptoms in ADHD, with good tolerability and few
adverse events.
•The dose ranges from 1.2 to 1.8 mg/kg/day in children and
between 60 and 120 mg/day for adults greater than 70K. The drug
is rapidly absorbed, with a half-life of 5 hours.
•Atomoxetine is a highly selective norepinephrine reuptake
inhibitor that has a mechanism of action different than the
stimulant drugs, making it unique among medications approved
for the treatment of ADHD.
•Some understanding of the mechanism of action is valuable, as it
will clarify issues relating to efficacy, tolerability, and side effects.
•Atomoxetine is a potent inhibitor of presynaptic
norepinephrine reuptake. Bymaster and colleagues performed
an experiment using rat prefrontal cortex brain tissue to
identify atomoxetine receptor affinity and, simultaneously,
demonstrate the brain area of greatest activity.
• Atomoxetine was shown to have an affinity to norepinephrine
but minimal affinity for serotonin (5-HT) or dopamine
transporters and neuronal receptors. Extracellular
concentrations of norepinephrine and dopamine were
increased 3-fold by atomoxetine
•In the prefrontal cortex (ie, the key region for executive
function, including attention and memory), in a dosedependent manner, but did not alter 5-HT levels or
significantly affect dopamine outside of the prefrontal cortex.
•Furthermore, atomoxetine was tested on over 60 other
neuronal receptors, transporters, and binding sites, without
finding any significant affinity.
•In contrast
to atomoxetine, the researchers found that
methylphenidate had a higher affinity for dopamine transporters
than for norepinephrine transporters.
• Like atomoxetine, methylphenidate increased extracellular
norepinephrine and dopamine equally in prefrontal cortex, but it
also increased dopamine in the striatum and nucleus accumbens
to the same level as in the prefrontal cortex.
• Interestingly, atomoxetine exhibited only small increases in
dopamine in the striatum and nucleus accumbens, which are the
areas of greatest concentration of dopamine transporters.
Stimulants are known to work via dopaminergic neuronal
pathways leading from the brain stem to the nucleus accumbens,
producing positive reinforcement.
• The fact that atomoxetine does not increase dopamine in this
region may relate to the demonstrated a lack of abuse potential
•The most common drug-related event reported across
trials has been gastrointestinal effects, such as nausea. A
decrease in appetite is experienced by 15% to 20% of
patients, with an initial period of weight loss that seems to
appear early in treatment and then declines.
•Atomoxetine has also been associated with slight
increases in diastolic blood pressure and heart rate, but
no effects were seen on cardiac conduction or the QTc
interval. The mild cardiac effects are comparable to the
effects reported with stimulants and ADHD medications
should be used with caution with patients at risk of
hypertension.
STRATTERA should not be taken with an MAOI, or within 2
weeks after discontinuing an MAOI. Treatment with an MAOI
should not be initiated within 2 weeks after discontinuing
STRATTERA. With other drugs that affect brain monoamine
concentrations, there have been reports of serious,
sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma)
when taken in combination with an MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Such reactions may occur when these
drugs are given concurrently or in close proximity.
Albuterol --STRATTERA should be administered
with caution to patients being treated with
systemically-administered (oral or intravenous)
albuterol (or other beta 2 agonists) because the
action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors --Atomoxetine is primarily metabolized
by the
CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs,
selective inhibitors of CYP2D6 increase atomoxetine
steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment
of STRATTERA may be necessary when
coadministered with CYP2D6 inhibitors, e.g.,
paroxetine, fluoxetine, and quinidine
•The various stimulant formulations seem to be quite similar in
their efficacy. However, the short half-life of the original
formulations required multiple daily dosing.
•In recent years, long-acting formulas have been put on the
market, ameliorating the stigma, inconvenience, noncompliance,
and rebound associated with a short duration of action.
• The newer extended-release agents are effective for as long as
10 to 12 hours, yet some patients are still requiring additional
short-acting stimulants to extend their treatment time.
• The current doses that are available are often too low for adults,
requiring them to take several pills and sometimes this means
paying considerably more for the medication or having the needed
dose refused by the insurer.
Methylphenidate vs Amphetamine
Amphetamine
Methylphenidate
Absorption
Acidic foods limit absorption
Readily absorbed;
independent of pH
Distribution
Low plasma protein binding
Low plasma protein binding
Metabolism
pH of urine determines
degree of hepatic clearance
Presystemic metabolism
limits oral bioavailability
Moderate P450 metabolism,
some CYP2D6
Elimination
Little P450 metabolism; no
CYP2D6 metabolism
Acidic urine results in
Elimination of MPH
decreased plasma half-life
metabolites unaffected by
and increased renal clearance urinary pH
Shows up on routine drug
testing
not show up on routine
drug testing
Does
Newer Stimulants
Vyvanse (lysamphetamine)
-dosages 10 ,20,30,40,60,70 mg
ZENZEDI
-dosages 5mg, 7.5mg, 10mg.
Quillivant liquid MPD
10ml = 4 mg
Selection of the Optimal Dose
Ratio for Metadate® CD
Methylphenida te (ng/mL)
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
Time after dose (hours)
1Wigal
et al. J Appl Res 2003;3:46-63
Ritalin (10 mg, bid)
20:80 prototype (25 mg)
30:70 prototype (25 mg)
40:60 prototype (25 mg)
22
24
Methylphenidate (ng/mL)
Biphasic Release Pattern of
Metadate® CD Capsules
20
16
12
8
4
0
0
1
2
3
4
5
6
7
8
Time after dose (hours)
Ritalin (10 mg, bid)
20 mg Metadate CD (30:70)
40 mg Metadate CD (30:70)
1Metadate®
CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing
Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)
2Wigal et al. J Appl Res 2003;3:46-64
9
•Generally, stimulant medications are well tolerated. Side effects
from stimulants include insomnia, headaches, weight loss or
anorexia, tics, anxiety, and dysphoria.
•Cardiovascular effects typically involve only mild increases in
heart rate and blood pressure, but need to be more closely
watched in adults than in children
•.Adults who present with borderline hypertension may not be able
to tolerate even a mild increase. In this circumstance the
hypertension should be treated before stimulant is reinstituted.
• Insomnia is common for adults with ADHD both before and after
initiation of a course of a stimulant. A delay in sleep onset may
decrease with longer administration of the medication.
• Stimulant medication is initially administered by titrating the dose
until symptoms are well controlled and, concurrently, side effects
are manageable for the patient.
•Both methylphenidate and dextroamphetamine are C-II controlled
substances and much has been written in medical and popular
literature about their potential for abuse, necessitating clarity on
the issue.
•An adult who suffers from ADHD, uses the medication as
prescribed, and does not concurrently have a substance abuse
problem will not become addicted.
•There are reports of stimulant medication prescribed medically
being diverted for nonmedical recreational use. Clinicians should
therefore be circumspect in prescribing medication to patients with
current substance abuse, or whom they suspect might sell the
drug.
•Interestingly, some studies offer intriguing evidence that stimulant
treatment of ADHD does decrease the risk of future substance
abuse, including cocaine use, among adult ADHD sufferers.
Key points:
•Pharmacotherapy is a central element in the treatment of ADHD,
and some studies have shown it to be more effective than
behavioral treatment in reducing the symptoms of ADHD.
Stimulants increase dopamine and norepinephrine levels in the
synapse, ameliorating symptoms associated with ADHD in about
70% of patients.
Side effects from stimulants can include hypertension, insomnia,
headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
When prescribed and taken appropriately for the treatment of
ADHD, stimulant medication is not addictive. Care should be
taken when using stimulants to treat patients with a comorbid
substance abuse disorder.
Other Stimulant Medications
Desoxyn (Methamphetamine Hcl)
Adipex-P (Phenteraimine)
Didex (Benzphetamine)
Tenuate (Diethylpropion Hcl)
Mazindol (Imidazoisoindol)
Phenazine (Phendimetrazine
Tartarate)
Dopram (Doxapram Hcl)
Alpha 2 adrenergic agonists
Clonidine
Adverse effects, sedating,
hypotension
Guaifenesin
Adverse effects - few & less
sedating
*Both are often used in combination
with other medications to augment
Desipramine (Norpramin), a tricyclic antidepressant that blocks
norepinephrine and serotonin uptake, and bupropion (Wellbutrin),
an antidepressant with greater dopamine reuptake block than
most antidepressants, have been shown to have some
effectiveness in treatment of ADHD.
Prozac
Paxil
Zoloft
Tofranil
Effexor SR
Lexapro
Generally Maximum benefit in co- morbidity
Melatonin
Melatonin may be helpful for treating
delayed sleep onset in children with
attention deficit-hyperactivity disorder
(ADHD),
Since melatonin is in an unusual category,
being an unpatentable hormone
considered in the U.S. to be a 'nutritional
supplement' that is unregulated by the
[Food and Drug Administration], and since
there is evidence that some brands
contain other than 'pharmaceutically pure'
melatonin, evidence of safety and efficacy
is of great importance to clinicians
Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool,
New Therapy and New Hope for ADHD
•Transcranial magnetic stimulation (TMS) is a newly
developed tool for assessing functionality of the central
nervous system (CNS). After Baker et al. demonstrated its
value in humans in 1985, single and paired-pulse
•TMS have proven useful in detecting clinical and subclinical
abnormalities in a large array of neurological and
neuropsychiatric disorders including Tourette's syndrome,
obsessive compulsive disorder, depression, schizophrenia,
bipolar disorders and ADHD among others.
•Regarding ADHD specifically, TMS seems to be an ideal
method for studying the maturational process of the motor
pathways since it clearly excites the corticomotoneuronal
system presumed to be involved in this disorder.
•Using single stimulation in children with ADHD, found a
prolongation of central motor conduction time as well as some
side-to-side stimulation differences compared with those found in
age- and sex-matched controls. These findings demonstrated a
delay in the maturation of the corticomotoneuronal system in
patients with ADHD.
• Moll et al.[11] reported that children with ADHD had significantly
reduced intracortical inhibition (ICI) with a normal intracortical
facilitation compared to healthy controls and such ICI showed
improvement after giving 10 mg of MPH.
•However, most of the morphophysioneurochemical hallmarks of
ADHD involving prefrontal-caudate-cerebellar pathways with
noteworthy dopaminergic abnormalities have not yet been taken
into account. Therefore we consider that they should be the
current focus if rTMS is to be employed as a therapeutic option.
•rTMS has been found effective in Parkinson disease, depression,
obsessive-compulsive disorder, Tourette's syndrome and some
types of tic.
• With regard to children rTMS has been tried with a small number
of patients with action myoclonus, progressive myoclonic epilepsy,
bipolar disorder, major depression and schizophrenia with some
promising, albeit, short-lasting positive results.
• Some of these disorders are due to dopamine abnormalities and
share some genetic, clinical, biochemical, neuranatomical and
neuro-behavioural similarities with ADHD.
• Even though a complete understanding of the mechanism of
action of rTMS has not been developed, it is now clear that rTMS
at low frequencies could cause long-term depression of corticocortical transmission in normals as well as improvement of
symptoms of some neuropsychiatric disorders commented on
above, including the modulation of several neurotransmitters such
as dopamine and its metabolites (e.g. homovanilic acid) mainly
after prefrontal cortex stimulation.
•Some safety issues must be considered in some of patients since
there is a limited experience of possible side-effects in children
and adolescents using TMS particularly rTMS.[] Even though
muscle-tension headache that resolved promptly is the only only
side-effect found in children receiving rTMS,
•Tis still concern in applying it with pulse frequencies of 50 Hz or
more for periods of several seconds because of the possiblity of
seizures.
• At present, there is no reason for applying rTMS at higher
frequencies, intensities or with longer train durations than those
employed in clinical or research studies.
• Thus, frequencies lower than 50 Hz might be used with some
confidence in humans until new safety guidelines on rTMS
applications can be published
ADHD
Parent
Information & education
Child management skills
School
Evaluation / PPT (Pupil Placement
Team)
Teacher training / Special education
School Nurse
Doctor
Diagnosis
ADHD
Role of School
Evaluation-medical & psychological
PPT (Pupil Placement Team)
Learning Disability definition &
placement
Teacher Training in ADHD
Teacher documentation( changes
with treatment, feedback to
Parents etc)
School Nurse -medication
documentation & dispensation
ADHD
Contingency management : point
token, reward systems- time out
Cognitive Behavioral training
(self monitoring,verbal self
instruction solving strategies, self
reinforcement)
Parent training /child management
skills
•Hallmark characteristics of attention-deficit
hyperactivity disorder (ADHD) include hyperactivity,
impulsiveness, and inattentiveness.
•Research has established that ADHD, still the most
common psychiatric disorder in children, can persist
not only through adolescence but into adulthood as
well.
• While ADHD can remit, an estimated 30% to 70% of
childhood ADHD cases continue into adulthood.
However, much of what we know about ADHD comes
from the wealth of research that has been collected on
its manifestations
• In childhood. Increasingly, evidence points to a
developmental shift in the presentation of ADHD in
adults. This shifting profile may well have resulted in
underdiagnosis of adult cases of ADHD.
ADHD is a developmental disorder, which by definition
must have been present from childhood. Many of these
adults may not have had the opportunity to be assessed
or diagnosed, since ADHD services and expertise may
not have been available.
More recently investigators have shifted their focus of interest towards
understanding the nature of attention problems and the executive
functions. Executive function refers to skills such as working memory,
planning, prioritization, organization, and time management. The
theory holds that the prefrontal lobes, which are associated with
memory, motivation, and synthesis of behavior, are the site of the
brain's executive function and regulate behavior via a process of
inhibition. Advances in neuro imaging technology and the
development of neuropsychological assessments have permitted
researchers to measure and quantify executive function in adults with
ADHD as compared with controls.
Many of the associated symptoms of ADHD
involve dysregulation of sleep, appetite, energy,
and mood that are easily understood within the
framework of mood disorders with which adult
psychiatrists are more familiar.
Most patients with ADHD also have another
comorbid disorder. The adult psychiatrist may
attribute the patient's impairment to the comorbid
disorder more familiar to him (ie, anxiety disorder,
bipolar II disorder, or personality disorder) and
miss the contribution of the ADHD.
Some of the comorbid disorders that accompany
ADHD are developmental disorders in their own
right that adult psychiatrists do not recognize such
as Asperger's syndrome, learning disabilities,
Tourette's syndrome, or oppositional defiant
disorder
The research that identified the continued prevalence of ADHD in
adults had also identified a pattern of lifelong adaptive functioning
difficulties. The maladaptive patterns might manifest with or
without comorbidities -- each topic will be covered in sections to
follow. What began as a problem functioning in the classroom and
playground became persistent social and vocational troubles, if
not failures. Research has demonstrated that adult ADHD is
associated with functional impairments that result in an array of
problematic behaviors, such as increased traffic accidents and
violations, difficulty with smoking, educational and occupational
impairment and marital problems.[
] In addition, ADHD was shown to predict specific disorders in
adulthood, such as antisocial behavior and substance abuse.[11]
Given the studies showing that patients who receive
pharmacological treatment have an 85% reduction in risk for
substance abuse, it is unfortunate that establishing validity of
ADHD in adults was so lengthy a process.
Key points:
It is well established that ADHD affects some
individuals across their lifespan.
Prospective studies illustrate that adults diagnosed
with ADHD as children retained at least one ADHD
symptom into adulthood.
Sequelae of ADHD may continue to impair the lives of
individuals with ADHD throughout adulthood,
particularly those who have not received treatment.
Key points:
Hyperactivity tends to decrease with age, while
problems with sustained attention persist and
predominate the symptom profile in many adults.
Adults exhibit impairments in the brain's executive
function both at home and at the workplace.
While all 3 core symptoms can persist over a lifetime,
adults with ADHD may have more attenuated
symptoms that are expressed in manners different
from children
•It is estimated that nearly 75% of adults with ADHD have a
comorbid condition, with reports ascertaining that 77% of this
population has had at least 1 of 17 comorbid psychiatric disorders.
• Comorbidity immeasurably complicates the diagnosis of ADHD
and, as will be discussed in the section on diagnosis, is not
excluded for an accurate diagnosis of ADHD, according to DSMIV criteria. The inclusive standard is likely based on an
accumulation of research,
•Indicating that the comorbidities are indeed discrete conditions in
their own right. As one group of researchers states, "among
adults, ADHD does not appear to be an artifact of symptoms
shared with other psychiatric disorders (eg, major depression,
bipolar disorder, generalized anxiety disorder) nor are the
comorbidities themselves the result of symptomatic overlap with
ADHD.
Key points:
Approximately 75% of adults with ADHD have at least 1 comorbid
condition.
Learning disabilities and disruptive behavior disorders are the 2
comorbid conditions most prevalent in childhood.
Adults with ADHD are at considerable risk for substance abuse
(especially marijuana), and smoking, but this risk is diminished by
appropriate treatment.
Mood and anxiety disorders are significant comorbidities among
adults with ADHD but more research is needed to determine their
prevalence.
While researchers may disagree about age of childhood onset in diagnosing adult
ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from
childhood. An assessment of ADHD symptoms and behavior from childhood may include
any or all of the following:
The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had
ADHD in childhood.
School report cards, if available, might include comments about behavior problems, poor
focus, lack of effort, or underachievement relative to the student's potential.
Parents may serve as collateral informants and complete an ADHD scale with respect to
the individual's symptoms in childhood.
The adult may self report symptoms in childhood on a diagnostic interview or on an
ADHD scale completed for childhood symptoms.]
The developmental history would be consistent with ADHD, including evidence of
problems with peers, other delays such as enuresis, school failure, suspensions, or
special interventions such as sitting in front of the class, etc.
Symptom rating scales.
Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps
the best scale available to discriminate between patients with ADHD and those with
other conditions; internal reliability and validity ratings are high (available from MultiHealth Systems at mhs.com).
DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for
oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.
The patient rates each item as:
0. Not at all or never
1. Somewhat or sometimes
2. Pretty much or often
3. Very much or very often
Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of
inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be
considered to have met the DSM-IV categorical cutoff. Several versions of this scale are
available, and 1 is available on the net. Barkley has adapted this scale for use with
adults.
•Neuropsychological assessments were initially developed for
children and established that children evidenced clinically
significant deficits in executive functioning, even when IQ
scores were above average.
•Neuropsychological assessments performed on adults with
ADHD reveals deficits in speed, memory, and attention.
However, research on these measurements demonstrates that
the spectrum of deficit functions associated with ADHD is not
consistent across the various neuropsychological tests
available for adults.
•Therefore, neuropsychological testing of adults may
contribute to an overall evaluation but, again, should not be
used as the sole diagnostic instrument. The same is true for
computerized tests of attention such as the Continuous
Performance Test (CPT) or Test of Visual Attention (TOVA).
•Compared with children who have problems in both
cognitive and behavioral control, adults with ADHD have
greater deficits in the use of executive functions relating
to cognitive control.
•As the years pass, the 3 core dimensions of the
disorder do persist in some form.[] However, the
demands on the brain's executive function to regulate,
organize, and manage behaviors both at home and at
the workplace become ever more complex.
•Experts suggest that failure of the brain's executive
functions is 1 of the most prominent attributes in adult
ADHD.
Hyperactivity -- not excessive action itself, but the inability to control
arousal and amount of activation
Inattentiveness -- not a global inability to focus per se, but rather the
inability to sustain, shift, and establish attention to particular tasks the
individual finds boring but are nonetheless essential to adult functioning
Impulsiveness -- no longer the inability to control actions, but the
inability to determine when and how actions should be expressed and
sequenced, and continued environmental dependency where
circumstances control action, rather than the other way around
Cognitive Therapy
GOAL
FOCUS “Now”
Requirement
“Stray”
Deflection
‘Thought”
Potentials
Nebula
Plague