Transcript ADHD: clinical neurosciences

Working with difficult children:
Recent advances in ADHD
Eric Taylor
King’s College London Institute of Psychiatry
There are many ways in which children can be ‘difficult’: ADHD is
just one. Behaviour is dysregulated : inattention, executive
dysfunction, altered response to reward, poor time perception, and
response disorganisation can all be involved. Assessment can guide
education, help counselling, and lead to treating ADHD.
Lessons from research
It’s not their fault
 Psychological treatments work
 Medicines help the worst affected
 Increasing range of medicines
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Conflicts in understanding ADHD*
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Great differences over
time
Great differences in
prevalence between
countries
Emotional &
behavioural problems
Performance variable
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Genetic influences 80%;
Frontal, striatal,
cerebellar parts of brain
are small
Same structures
underactivate
Psychological deficits
Persistent and pervasive abnormalities in : Attention (distractible,
forgetful, disorganised); Activity (restless, fidgety) and Impulsiveness
(acting without thinking)
Where does ADHD come from?
Twin studies show high heritability
DZ
MZ
Twin
correlatio
ns
Median heritability (13 studies) 0.82 (0.52-0.98)
Search for high-risk alleles
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DRD4
7 (vs 2-5 or 8) copies of 48 bp VNTR on 11p.15.5
 metaanalysis
p< .00000001
 Odds ratio (averaged): 1.32
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DAT1
9 vs 10 copies of 40 bp VNTR on 5p15.3
 metaanalysis
p<.0001
 Odds ratio (averaged): 1.13
8 candidate genes well established to be associated with ADHD:
mostly affecting dopamine or serotonin neurotransmission
Geographical variations in the number of repeats
of the variable 48-bp sequence in DRD4
Chang et al
Genome scan identifies a spot on Chr 16: Cadherin 13
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Cadherins mediate cell adhesion and play a fundamental role
in normal development. They participate in the maintenance
of proper cell-cell contacts
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CDH13 also implicated in substance misuse:
Nicotine dependence
Substance dependence
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Plays a role in cell adhesion, cell-cell contacts and cellmigration
What is inherited?
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Not ADHD: genetic influences on continuum*
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Not a unitary trait: influences vary with context
Dispositions to react:
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 gene-environment
interactions and correlations
early physical environmental associations
 parenting influences on development
 MAOA multiplies effects of violence, DRD4.7/DAT10 of
smoking
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*(with possible exception at highest level of severity & possible latent
classes)
Probable environmental associations
Pregnancy
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nicotine, alcohol, anticonvulsants, cocaine
lead, mercury; thyroid, immune rejection
stress; infections; toxaemia;APH
Perinatal
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low birth weight, O.C.s, perinatal care, [season of birth]
Infancy
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attachment problems, neglect, injury
socioeconomic adversity, nutrition
Childhood
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Course influenced by exclusion, hostility, injury, school
But, if ADHD is so neurological, how
come it varies so much in different
places? Isn’t it really a social disorder?
What about the rise of television and the
decline of the family?
Prevalence of disorder
ADHD
/1000
Numbers per 1000
50
40
30
Real
prevalence
20
10
0
US'80
UK'80
US'98
Admin prevalence
UK'99
Hyperkinetic disorder
Administrative prevalence from local surveys; HKD in approx 105,000 nationally
Numbers per 1000
Prevalence of disorder
70
60
50
40
30
20
10
0
HK
ratings
HK ratings
UK
diag
UK ratings
Same survey method in Hong Kong and East London
HK diag
UK diag
Is it a Social Problem?
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Does society determine the presence of ADHD?
 No,
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shared environment plays little part
Does society alter the rate?
 Only
small differences between societies
 Little increase over time
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Does society determine what is recognised?
 Yes,
substantial cultural differences
Is it a Treatable Problem?
Patterson - OSLC
Interventions in the classroom
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Proximity to teacher
Managed transitions
Pacing & letting off energy
Classroom aide
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operant conditioning
peer advice
Rule government
Clarity of goal & speed of feedback
Understanding disorder (eg projects)
Monitoring medication
Some common-sense procedures – avoiding distractors
and short-chunk learning – don’t yet have trial evidence
Specific treatments
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Psychological therapies:
Parent training, behaviour mod, social skills
Licensed drugs:
Methylphenidate, dexamfetamine,
atomoxetine
 Unlicensed drugs:
Trial evidence: pemoline, imipramine, clonidine, bupropion,
“Adderall”, modafinil, guanfacine
Anecdotal: moclobemide, risperidone, sertraline
 Diet: eliminations and supplements

Include non-specific interventions - education, support, advice
A range of presentations: Xavier
Xavier, aged 11, has been out of the control of his
parents after an episode of meningoencephalitis at age 4.
He is dangerously aggressive to his sister and younger
brother and has been excluded from a special unit at
school. He sets fires, steals from shops, and puffs
cannabis with a group of older boys.
He can’t concentrate in class, is very forgetful and
disorganised; and teachers have believed that this comes
from a chaotic home background.
A complex disorder, multiply caused
Not just bad parents: Medication of child reduces parental EE
Not just complications:
In never-medicated adults:
Recent findings of low
dopamine and DAT
Recent findings of
persisting hypoactivation
Not just genetic: The Environmental Risk Longitudinal
Twin Study interviewed the mothers of 565 five-year-old
monozygotic (MZ) twin pairs : the twin receiving more
maternal negativity and less warmth had more antisocial
behavior problems. (Moffitt et al 2008)
A range of presentations: Matteo
Matteo is regarded by his parents as a charming 8-year-old
who has recovered from injury but is now encountering
bullying. His teachers, however, refer him to the clinic
with a very different story: he does not listen to them, he
does not concentrate as he should, he has low academic
self-esteem and big tempers when frustrated, he is inclined
to lose his way, he is clumsy and his handwriting is
terrible.
He was popular when he started at school, but now is
teased a great deal. His teachers are frustrated because in
individual sessions he shows good understanding and
creativeness.
A complex disorder, multiply caused
Inattention creates an
increasingly
unstimulating
environment
Effect sizes on ADHD scales
1.2
1
0.8
Parent effect
Teacher effect
0.6
0.4
0.2
0
MPH- IR
Concerta
Equasym ATOMOX
Psychological interventions
Type
Parent training
Delivery
Costed as:
Group
10 sessions
Individual
10 sessions
Group + child
Cognitive
Individual
Educational
Class information Delivery to teacher
Screening
n/a [no effect]
n/a
Principles of psychological
treatment
Identify specific problems
 Analyse contingencies
 Enhance adult attending
 Teach effective instruction
 Token economy + response cost (frequent)
or time-out + rapid novel rewards
 Include self- management
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A school-based trial
Tymms & Merrill (2009)
86 schools & 2,584 pupils in randomised trial
Year 2 behaviour in schools receiving an Information Booklet was improved
(ES = 0.26)
Pupil attitudes to school and reading were improved (ES = 0.17)
No effect of screening programme.
Cost of booklet £2.55
(similar booklet in Taylor E (ed) People with Hyperactivity. CDM 171; MacKeith Press)
Learning social skills in peer group
Listen to others
 Join play gradually
 Learn the rules
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 Avoid
intrusiveness and excessive demands
Figure out why others react
 Control anger
 Learn how to refuse kindly
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 Especially
drugs
But do behavioural treatments
work? Metaanalysis
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Pelham & Fabiano (2008) review:
 Behavioural
parent training
 Behavioural classroom management
 Intensive intervention in recreational settings
Journal of Clinical Child and Adolescent Psychiatry 37 184
NICE approach: Systematic
literature review
Table 5. Databases searched and inclusion/exclusion criteria for clinical evidence
Electronic databases
CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO
Date searched
Database inception to 18.12.08
Study design
RCT
Patient population
Children diagnosed with ADHD
Interventions
Any non-pharmacological intervention used to treat ADHD symptoms and/or associated
behavioural problems
Outcomes
ADHD symptoms*; conduct problems*; social skills*; emotional outcomes*; self-efficacy*;
reading; mathematics; leaving study early due to any reason, non-response to treatment.
*Separate outcomes for teacher, parent, self, and independent ratings.
Cost-effectiveness calculation
Table 10. Cost-effectiveness of parent training versus no treatment in
children with ADHD - results of the base-case analysis over 1 year
Total QALYs /
child
Total cost / child
Parent
training
0.803
£168
No treatment
0.785
0
Intervention
ICER
Parent training versus no
treatment: £6,608/QALY
Sensitivity analyses for differing assumptions
Economic conclusion
According to this analysis, and after assuming an 80%
uptake of such programmes,
the group clinic-based programme resulted in a cost per
responder of £10,060 and £1,006 at a 5% and 50% success
(response) rate, respectively; and a cost per QALY of
£12,575 and £3,144 at a 5% and 20% improvement in
HRQoL, respectively.
Clinical conclusions
The results of the economic analysis indicate that
group-based parent training programmes (or CBT for
children of school age) are likely to be cost-effective for
children with ADHD, if the mode of delivery of such
programmes does not affect their clinical effectiveness.
Individual parent training is unlikely to be a costeffective option
Neurofeedback trials meta-analysis
Month
0
Recruitment
Screening
Diagnosis
579 Subjects
7 to 9 yrs old
ADHD-Combined
Pre-Baseline
R
A
N
D
O
M
A
S
S
I
G
N
M
E
N
T
Baseline
14-m
Treatment
Phase
14
10-m
Follow-up
Phase
24
22-m
Follow-up
Phase
36
MedMgt
144 Subjects
Beh
144 Subjects
Comb
145 Subjects
CC
146 Subjects
End of
Early
MidTreatment Treatment Treatment
(14 m)
(3 m)
(9 m)
First
Follow-up
(24 m)
Observation 1
LNCG Group
Assessment Points
Second
Follow-up
(36 m)
Observation 2
LNCG Group
Comparing Therapies:
Conclusions from MTA Study
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Medication is more powerful than behavioural
treatment at 14 months
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Research treatment better than routine
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Many advantages in adding medication
to behavioural treatment; few in adding
behavioural treatment to medication
Comparing therapies:MTA Timeline
Study
Treatments
Randomisation ends
36 Month Findings on Substance Use
Molina et al
Jensen et al, 2007
Intent-to-treat (ITT) Analysis
MTA Group, 1999a,b
MTA Group, 2004a,b
Randomized Clinical
Trial at 14-month
assessment: Transition
to Naturalistic Follow-up
at the 24-month & 36month Assessment
Equifinality of Interventions:
How Should Clinical Services React?
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Results underestimate treatment effects?
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Treatments lack long-term benefit?
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Extra benefits of intensive therapy fade?
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Self-selection makes good outcomes
Subtyping
ANXIETY / DEPRESSION
IMP
1/4
SCHOOL
HOME
HKD
INAT
6/9
HYP
3/5
IMPAIRMENT
ADHD versus HKD
ANXIETY / DEPRESSION
IMP
1/4
SCHOOL
HOME
HKD
INAT
6/9
HYP
3/5
IMPAIRMENT
SNAP Hyperactivity-Impulsivity
(Parent)
SNAP Hyperactivity-Impulsivity
(Parent)
SSRS Total Social Skills (Parent)
Economic modelling
Continue
QoL
Methylphenidate
Parent training
Methylphenidate
Parent training
Continue
£
Severe cases
Continue
Methylphenidate
Parent training
Methylphenidate
Relative effect of medication to behavioural
interventions greater in hyperkinetic subtype
Parent training
Continue
Treatment decisions
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Severe, pervasive, disabling?
Problems at home?
?
 Problems at school?
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Home CBT
Liaison
+ self-instruction
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Persistent after treatment?
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Comorbid problems?
Medication
Key recommendations from NICE
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ADHD should be recognised and referred
 Comprehensive specialist assessment; impairment req’d
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Trusts to set up lead group
Adult services to be developed
First choice usually group parent training
Severe cases go straight to medication
First choice medication usually MPH
Shared care expected
Drugs or behaviour therapy?
Conclusions so far
Both are effective
 Both are cost-effective
 Medication hazards:
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 Growth
suppression (manageable)
 Hypertension (avoidable with monitoring)
 Unknown risks to CVS
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ADHD is heterogeneous in severity and
course
Specific approaches: cognitive therapy
Effective for coexistent anxiety/ depression
For Core ADHD symptoms, little effect:
Learning to STOP AND THINK
Recognising and managing anger
Teaching others to be self-controlled
Tolerating waiting
So far, trial evidence suggests no effect on core ADHD. What are we doing wrong?
Perhaps teaching cognitive control is
hard because there are many routes
into impaired control/ impulsiveness
Varieties of “inattention”
Planning
Reaction time,
Continuous performance tests
CPT with distractors
Central-incidental learning
Dual task
“Inhibition”, preparedness,
Sternberg, cognitive energetics
Attention domains
 Executive function
 Alerting
 Sustaining vigilance
 Resisting distraction
 Altering focus
 Allocating resource
 Modify responsiveness
A continuous performance test
Press
% errors
A sustained attention deficit?
12
10
8
6
4
2
0
ADHD
Control
Beginning of
task
End of task
Number of errors are high and responses slow throughout the test
eg Sergeant et al 1990
% commission errors
Slowing the presentation rate
9
8
7
6
5
4
3
2
1
0
2 seconds
ADHD
Control
8 seconds
Van der Meere et al 1995
A preparation deficit?
1.2
1
0.8
ADHD
Control
0.6
0.4
0.2
0
1 second
Warning
15 sec
Signal
30 sec
RT
Response
Sonuga Barke et al 1993
GONOGO
press
inhibit
Selective inhibition of a
motor response/response
selection
REVERSAL
press
STOP
inhibit
press
inhibit
ISI: 1.6s
Withholding of a planned motor
response
SWITCH TASK
Modification of Meiran Switch task: Cognitive flexibility.
Switching between two dimensions.
Delay of gratification
Useful clinical test in preschool children; needs to be subtler for
Post - reward delay
1p
?
1p
30 sec
?
?
2p
Experiments by Edmund Sonuga-Barke
Delay aversion v inhibition
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Evidence for both; inhibitory failure in more
severe cases
Combination of both predicts behavior much more
strongly than either alone (Solanto et al)
Inhibition (5-choice serial RT; 5HT2A,C) and preference for
delayed reward (5HT2C,B) show double dissociation
with 5-HT receptor (Talpos et al)
Reward & Social Influences
Time scales of reward effects
Response to reward
Expectation
Previous reward history
Reinforcement
schedules
Anticipation
Effects
Pairing
Choice between alternatives
Rapid change of activity
REWARDED CPT
 FMRI: respond to “X” and “O”. ISI: 900ms
Specific dysfunctions in CD vs ADHD
Sustained Attention
Reward
‘Reward’ Problems presented in
psychopathology
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Misbehaviour (“oppositional/conduct disorders”)
Anhedonia
Misery
Addiction
Hunger for novelty/sensation/reward/dopamine
Apparently dysfunctional choices (risky or
punished activities)
Insensitivity to reward schedules
Clinicians use of reward
mechanisms
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Parent Training
 Clarity,
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
consistency, speed
Premack principle
Reward schedules
 enuresis
training
 reward frequency before training
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Reward novelty
[Density, predictability, reward/punishment ratios]
Clinicians’ use of punishment
mechanisms
Reduction of naturalistic punishment
 Response cost
 (Time-out)
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 Conceptualised
as extinction
What is it like to be inattentive/ impulsive?
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“My thoughts are in a muddle”
 (usually
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only after treatment shows the difference)
“I get into trouble a lot, I don’t know why”
“Other kids pick on me”
“Ive got a bad temper”, “I cant concentrate”, “Ive
got ADHD”
(usually repeating what they have been told)
Conclusions
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There are several testable cognitive dysfunctions

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They are found in several presentations


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Attention deficit, impulsiveness, irritability
Useful for individual analysis, not diagnosis

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Response organisation, switching, reward, timing
But most tests are unstandardised
Could help to guide teaching
Treatment does not usually depend on cause

Consider behaviour modification and medication
Research knowledge on ADHD
Common, persistent, risk for mental health
 Neurobiology becoming clearer

 Low
dopamine levels in striatum (PET)
 Frontostriatal (& other) brain changes (MRI)
 Genetic and environmental causes
• Allelic variants associated, esp genes in dopamine system

Effective treatments
 Stimulants,
atomoxetine, behaviour therapy
 Efficacy is not related to cause