Transcript Pharmacology Seminar 1. Pharmacokinetics

Pharmacology
Section 10.
Antidepressants and
mood stabilizing drugs
Marta Jóźwiak-Bębenista
[email protected]
Affective disorders
 psychiatric diseases
1. Major depressive disorder (MDD)
monopolar depression/ unipolar affective disorder
 Dysthymic disorder
 Seasonal affective disorder (SAD)
 Postpartum depression („baby blues”)
 Premenstrual dysphoric disorder (PMDD)
 Substance-iduced mood disorder
2. Bipolar affective disorder (BAD)
manic depressive disorder  alternating manic,
normal and depressive episodes
Depression
 everyone feels "blue" at certain
times
 transitory feelings of sadness are
perfectly normal
 clinical depression is a serious
condition that affects a person's
mind and body.
 all aspects of everyday life
including eating, sleeping,
working, relationships, and how a
person thinks about
himself/herself.
 cannot simply will themselves to
feel better or „snap out of it”
 symptoms can
continue for weeks,
months, or years at
untreated patients
Statistics and Information about
depression
 Depression affects almost 10% of
the population, or 19 million
Americans, in a given year
 During their lifetime, 10%-25% of
women and 5%-12% of men will
become clinically depressed
 Women are affected by
depression almost twice as often
as men
- hormonal changes brought on by
puberty, menstruation, menopause, and
pregnancy.
- suicide is serious risk for men with
depression, 4 times more likely than
women
 It can affect any
person at any age
(usually 25-44)
Statistics and Information about
depression
 Two-thirds of those who are
depressed never seek treatment and
suffer needlessly
-
personal weakness or character flaw
do not recognize the signs or symptoms that
something may be wrong.
 80%-90% of those who seek
treatment for depression can feel
better within just a few weeks
- one-third of those who are depressed
actually receive treatment
 Depression as the "common cold" of
mental illness.
The economic
cost of depression
is estimated to be
over $30 billion
each year
Symptoms of depression
 Emotional  usually worst in the morning
–
–
–
–
–
–
depressed mood most of the day, nearly every day
sad, anxiety or “empty” feelings
lack of pleasure in usual activities
no interest in the future.
restlessness, irritability, pessimism
feelings of guilt, worthlessness, helplessness, and
hopelessness
– difficulty thinking, such as concentrating or making
decisions, memory impairment
- recurrent thoughts of death or suicide
Symptoms of depression
 Physical (biological)
– change in sleep patterns.
 usually early morning awakening
 inability to sleep
 sleeping too much
– change in appetite and weight
 decreased appetite with weight loss (most common)
 sometimes increased appetite with weight gain
– loss of energy or fatigue
– unexplained physical problems:
 headaches, stomach problems, aches and pains,…
People who are depressed may not experience
all of these symptoms. Some will have many
symptoms, others will have just a few.
In order to make diagnosis of a major
depressive disorder, the symptoms
(five or more) must have been present
without a return to normality for at least
2 weeks.
Causes of depression
It is not fully known what exactly causes clinical
depression.
Numerous theories:
 biological causes
 genetic causes
 environmental influences
Clinical depression is most often caused by the
influence of more than just one or two factors.
Biological causes of depression
1. monoamine theory
The drugs, that will be increasing
neurotransmission, in aminergic
neuron systems will be used in
depression treatment.
2. Cortisol- hormone that the body
produces in response to stress
Depressed patients have
a raised baseline cortisol
concentration
Deficit of monoamines:
NA, 5-HT, DA in the brain
 Concentration in
the synaptic cleft
 Neurotransmission
in the brain
Biological causes of depression
inadequate neurotransmitter signalling
– functional deficit of NA, DA and 5-HT
(monoamine theory)
– desensitization of β-adrenergic and 5-HT2A
receptors
– dopaminergic system
– GABA
– peptidergic systems (AVP, opiates)
Reducing the central serotonin,
noradrenaline, and dopamine
concentration can lead to depression
Drugs that increase the central
serotonin, noradrenaline, and
dopamine concentration
improve depression!
Causes of depression
 genetic causes
- the result of what patients inherit from parents
- If one or both parents have a vulnerability to
depression, then it can be transmitted to their
children.
- if one identical twin suffers from depression or
manic-depressive disorder, the other twin has a 70%
chance
 environmental influences
- stress, breakup of important attachments (lack of
loving parents, death of a parent during childhood),
physical illness (medication, substance abuse)
Treating depression
1.
2.
Antidepressant drugs
Electroconvulsive therapy (ECT)
- success rate of 78%
- ECT for individuals whose depression is severe or life threatening
or is effective in cases where antidepressant medications do not
provide sufficient relief of symptoms
3.
-
Psychotherapy
learning about their disorder, learning to identify and avoid situations
that may induce another depressive episode, view themselves and
their situations more realistically, and to improve their interpersonal
relationship skills.
Herbal remedies
St. Johns Wort
 Derived from
Hypericum perforatum
 Most popular remedy in
the world
 Appears effective for
milder depression
 Side effects: phototoxicity
 available without
prescription
 900-1800mg/day is
recommended dose
Antidepressants
Antidepressants
Tricyclic
antidepressants
TCAs
Selective
serotonin
reuptake
inhibitors
SSRIs
Monoamine
oxidase
inhibitors
MAOIs
Mood
stabilizer/
other drugs
Antidepressants
Antidepressants
Tricyclic
antidepressants
TCAs
Selective
serotonin
reuptake
inhibitors
SSRIs
Monoamine
oxidase
inhibitors
MAOIs
Mood
stabilizer/
other drugs
Tricyclic antidepressants
 Since the 1950s
 Imipramine (Tofranil)
 Three-ring chemical structures
 Less popular choice than the new generation of
antidepressants
 Similar therapeutic efficacy
 Choice of drug (side effects/duration of action)
 Change of medicine after three weeks
Mode of action:
beefing up the brain`s supply of NA, 5-HT levels
Ø monoamine (NA, 5-HT) reuptake into presynaptic nerve from the synaptic
cleft  concentration of NE, 5-HT  neurotransmission
The antidepressant effect of TCAs occur after two weeks or longer of
continued treatment !!!
- decreased reuptake  immediate
effect  not the antidepressant effect
- long- term adaptational changes
in receptors
 the antidepressant effect !!!
- reuptake blocking
potency doesn’t
correspond with
clinical potency
 Ø receptors for ACh, HA, 5-HT, α
The important drugs of TCAs
 Tricyclic Antidepressants
(TCAs)
 amitriptyline (Elavil, Endep)
 clomipramine (Anafranil)
 desipramine (Norpramin,
Pertofrane)
 doxepin (Adapin, Sinequan)
 imipramine (Imavate, Janimine,
Presamine, Tofranil)
 nortriptyline (Aventyl, Pamelor)
 protriptyline (Vivactil)
 trimipramine (Surmontil)
 Heterocyclic Antidepressants
Second-generation
• amoxapine (Ascendin)
• maprotiline (Ludiomil)
Pharmacokinetics
1. Absorption and distribution
good absorption from GI tract upon oral
administration
lipophilic properties
good BBB penetration
long half-life (for imipramine 4-18 h)
first-pass effect  inconsistent and low
bioavailability
– patient’s response  dose adjustment
Pharmacokinetics
2. Fate
TCAs are metabolized by enzymes
Cyt.P450
metabolites pharmacologically active!
Amitriptyline  nortriptyline*
Imipramine  desipramine*
Active metabolites prolong
pharmacological effects
excretion  urine
Therapeutic uses of TCAs






severe depression - also prevents recurrence
depression with anxiety
panic and phobic disorders
bet-wetting in children (imipramine)
chronic or psychogenic pain
bipolar disorder
Side effects of TCAs
1.
antimuscarinic effects: dry mouth, blurred vision,
urinary retention, constipation and aggravation of
glaucoma and epilepsy
2.
postural (orthostatic) hypotension  reflex
tachycardia
3.
4.
5.
6.
cardiovascular (heart failure, hypertension,
hypotension, sudden death, arrhythmias, ECG
changes)
sedation
hormonal effects (loss of libido, impotence)
others: gastric irritation, weight change, allergic skin
reactions and jaudince
Contraindications to TCAs






prostate
narrow angle glaucoma
recent myocardial infarction
heart block, heart failure
arrhythmias
epilepsy
Drug interaction of TCAs
 MAOI  „serotonin syndrome” - life threatening!
tachycardia, hypertension, hyperactivity, hyperpyretic crisis,
convulsions, coma
TCAs should not be given in conjunction with- or within at
least two weeks of treatment with -a MAOI.
TCA+MAOI= monitoring!
 Drugs having anticholinergic actions
 Central nervous system depressant (alcohol,
barbiturates)
 Hepatic enzyme inhibitors (cimetidine, SSRI)
 Hepatic enzyme inducers (carbamazepine)
 Oral coumarin anticoagulants (increase effect)
 Guanetydyna (decrease effect)
Tolerance and withdrawal with
TCA’s
Tolerance generally develops to
anticholinergic and sedative side effects
within a short time
An occasional withdrawal syndrome is
reported with abrupt discontinuation from
high dosages.
True dependence, however, does not
occur
TCAs can be used for prolonged treatment
without loss of effectiveness
Tricyclic antidepressants
 (!) unmask manic behavior in BAD
 (!) low TI  suicidal attempts  acute
toxicity (arrhytmias, respiratory depression,
convulsions,…)
 monitored closely
Antidepressants
Antidepressants
Tricyclic
antidepressants
TCAs
Selective
serotonin
reuptake
inhibitors
SSRIs
Monoamine
oxidase
inhibitors
MAOIs
Mood
stabilizer/
other drugs
Selective serotonin-reuptake
inhibitors SSRIs
Introduced in the 1980s as a new
antidepressants
Replaced the TCAs
Affect the serotonin-containing nerves
safe, better tolerability, less severe side
effects
Less toxic in overdose than TCAs
Do not require blood monitoring
Mode of action of SSRIs
 Specifically inhibit 5-HT
reuptake from synaptic cleft
into presynaptic nerve
terminals
 concentration of 5-HT in
the synaptic cleft long term
adaptational changes 
serotonin
neurotransmission
 no effect on NE reuptake
 don`t have affinity for M, HA,
5-HT and α receptors
SSRIs include:
 - Citalopram (brand name: Celexa),




- Fluoxetine (brand name: Prozac),
- Paroxetine (brand name: Paxil)
- Sertraline (brand name: Zoloft)
- Fluvoxamine
Fluoxetine is now the most widely prescribed
antidepressant in the United States!
Pharmacokinetics of SSRIs
1. Absorption and distribution
 oral administration
 rapidly absorbed and distributed
 Active metabolites! –
citalopram, fluoexetine, sertraline
fluoexetine  norfluoxetine*
 Norfluoxetine is 3x more selective, potent than
parent drug
 fluvoxamine(+) no active metabolite  t0.5 ~ 15 h
fluoexetine t0.5 up to 30 days
The long half-life of fluoxetine and its metabolite
imposes cautious management when treatment
is to be changed, because the drug lingers in the
blood for some time after the treatment has been
discontinued,
this way increasing the risk of drug
interactions.
Side effects of SSRIs
SSRIs have fewer side effects than TCAs
(fewer anticholinergic effects and lower cardiotoxicity)
•
gastrointenstinal disturbances: nausea, vomiting, diarrhoea
•
headache, insomnia,
•
anxiety, agitation
•
sexual dysfunction (loss of libido, impotence)
•
allergic skin reactions
•
weight loss
•
tremors, seizures
•
serotonin syndrome!
Therapeutic uses of SSRIs:
 Clinical
 Efficacy similar to that
advantages:
of TCAs
- no anticholinergic
 Major depression
effects
- no orthostatic
 acceptability
hypotension
- no weight gain
- no toxic in overdose
- lower cardiotoxicity
Therapeutic uses of SSRIs:
1. depression in early stages
2. minor depressive illness
3. anxiety disorders:
- panic attacks
- obsessive-compulsive disorder
2. eating disorders (bulimia nervosa, anorexia
nervosa)
3. chronic pain (e.g. pain associated with diabetic
neuropathy)
4. menstrual syndrome
Drug interactions of SSRIs
- MAOI „serotonin syndrome”
It should wait at least two weeks between
stopping MAOIs and starting an SSRI, or at
least five weeks after stopping an SSRI and
starting an MAOI.
- TCAs monitoring!
- tryptophan (headache, nausea, sweating
and dizziness)
- warfarin (excess bleeding)
Drug interactions of SSRIs
SSRIs are inhibitors of hepatic cytochrome P450
isoenzyme!
metabolizes: -  neuroleptics,
-  TCAs,
-  some antiarrhythmics
-  beta blockers
paroxetine> fluoxetine> sertraline> citalopram>fluvoxamine
-
Hepatic enzyme inhibitors (cimetidine, SSRI)
Hepatic enzyme inducers (carbamazepine)
Antidepressants
Antidepressants
Tricyclic
antidepressants
TCAs
Selective
serotonin
reuptake
Inhibitors
SSRIs
Monoamine
oxidase
inhibitors
MAOIs
Mood
stabilizers/
Other drugs
MAOIs
Adverse reactions associated with MAOIs
are generally more frequent and severe
than with other antidepressants.
- reducing the dosage
- monitoring the patients
Use of MAO inhibitors is now limited,
because of the complicated dietary
restrictions required of patients taking
MAOIs!
Mechanism of action of MAOIs
Inhibit the action of monoamine oxidase- MAO
MAO-A
5-HT, NA
Tyramine
MAO-B
Dopamine,
phenylethylamine
1. irreversibly or reversible inactivation MAO
2. nonselective or selective - MAOI-A and MAOI-B
selective + reversible: moclobemide  less ADEs, INTs
Mechanism of action of MAOIs
Inactivation of monoamine oxidase
–  concentration of
NA, 5-HT, DA in the
presynaptic neuron
–  leakage of
monoamines into
synaptic space
–  monoamine
transmission
MAOIs:
1. Non-reversible/non-selective monoamine oxidase inhibitors
(MAOIs)

phenelzine - the hydrazine derivative, amphetamine-like activity.

isocarboxazid - the hydrazine derivative

tranylcypromine - non-hydrazine derivatives, amphetamine-like
activity.
2. Non-reversible/ selective monoamine oxidase inhibitors

Selegilina MAO-B
3. Reversible/ selective monoamine oxidase inhibitors

Moclobemid
Actions and Pharmacokinetics of
MAOIs
Actions:
 antidepressant action after 2-4 weeks
 amphetamine-like stimulatory
Pharmacokinetics:
 oral administration
 long duration after discontinuation of
treatment (~ 2 weeks)  irreversibly
inactivated
Washout period
 The irreversibility of the binding of the
enzyme by IMAO is a serious problem
 Effects of MAOIs continue until enough
new, unbound MAO is synthesized !
 Enzyme regeneration occurs several
weeks after the ending of treatment
 wash-out period of at least 2 weeks
should be allowed between stopping a
MAOI and starting a TCA or a SSRI
 During this 2 weeks the patients should
continue dietary and other restrictions
until this time has elapsed.
Therapeutic uses of MAOIs
 atypical depression (e.g appetite disorders)
 depression
– if unresponsive to TCAs
– if associated with strong anxiety
– if associated low psychomotor activity
 resistant depression
 facial pain
 phobic states
Adverse effects/interactions
of MAOIs
 tyramine rich food (cheese, red wine, beer,
chicken liver)  „cheese reaction”
– tyramine not inactivated by MAO   catecholamine
release  tachycardia, headache, nausea,
hypertension, cardiac arrhytmias, stroke
– develops within 30 minutes to 1 hour after ingestion of
the food
– antidote  phentolamine, prazosin
 Sympathomimetic agents (dopamine,
ephedrine), opioid analgesics, narcotics
 TCAs or SSRIs  „serotonin syndrome”
– washout period of ~ 2 weeks when therapy change
MAO blockade has the potential of serious and indeed
lifethreatening consequences if the subject is exposed
to certain agents, which would normally be metabolized
by this same
enzyme.
The patients treatment MAOI must therefore be
educated to avoid tyramine containing foods and
some drugs.
For these reasons, the MAOIs are no longer
considered as first-choice antidepressants and
are usually only prescribed after other options
have failed.
Foodstuffs (high in tyramine) to avoid with MAOIs

Drugs to avoid with MAOIs:
1. sympathomimetic agents, such as:
-dopamine
-ephedrine
-levodopa
-pseudoephedrine
2. opioid analgesics
3. amphetamine
4. dextromethorphan
5. CNS depressant (e.g alcohol,
narcotics)
6. SSRIs, TCAs
Other side-effects
a.
b.
c.
d.
e.
f.
Sleep disturbances, drowsiness
Orthostatic hypotension
Weight gain
Sexual dysfunction
Insomnia
Peripheral neuropathy (pyridoxine
deficiency)
Contraindications to MAOIs:



pheochromocytoma
congestive heart failure
liver disease
Antidepressants
Antidepressants
Tricyclic
ADs
Selective
serotonin
reuptake
inhibitors
Monoamine
oxidase
inhibitors
Other
drugs
Other drugs
Heterocyclic Antidepressants
The new generation drugs
•
•
•
•
Second-generation
bupropion (Wellbutrin)
trazodone (Desyrel)
amoxapine (Ascendin)
maprotiline (Ludiomil)
Third-generation
• mirtazapine (Remeron)
• venlafaxine (Effexor,
Efectin)
• nefazodone (Serzone)
Second generation antidepressants
Trazodone
- SSRI, Ø NA and 5-HT receptors
- may be used in schizophrenic patients
Maprotiline
- selective noradrenaline reuptake inhibitor (NARI)
Bupropion (Wellbutrin)
- selective dopamine reuptake inhibior,
antinicotine treatment
Third-generation antidepressants
Venlafaxine
– Serotonin-noepinephrine reuptake inhibitors
(SNRIs)
– clinical profile like SSRIs, quick onset of action
Mirtazapine
- noradrenergic and specific serotonergic
antidepressant (NaSSA)
- Ø presynaptic NA and 5-HT receptors
Nefazodon ~ trazodon, less sedating
Other atypical
antidepressants:
Mianserine
–presynaptic α2
blocker
–A: sedative,
anxiolytic
Tianeptine
– 5-HT reuptake
(???)
–(+) few ADEs
–ADE: hepatitis
(rare)
Viloxazine
– NE reuptake
–(+) not cardiotoxic
or cholinolytic
Drug choice
 The right drug and the right dose for the individual
patient must be accomplished empirically and
depends on:
- the clinical characteristics of the patient`s illness
- the drug`s adverse effect profile
- toxicity in overdosage and dosing schedules
- the past history of the patient`s drug experience
 The greater tolerability of the SSRIs and SNRIs,
NaSSAs make them the preferred agents for most
patients
 If there are no medical contraindications or no risk
of suicide, a TCA can be used
Drug choice
 MAOI – atypical depression
One third of patients do not respond to any
single treatment
 unresponsive patients
SSRI+TCA (desipramine) / Bupropion /
Mirtazapine
 lithium+SSRI
A generally accepted strategy is to
begin treatment with an SSRI in mild
to moderate outpatient depression
and then augment by adding a drug
of a different class for more impaired
patients
Bipolar disorders
also known as manic depression
or manic-depressive illness
Bipolar disorders
 Moods shift between two extremes
 For a period of time the person
experiences the symptoms of
depression (the depressive phase),
then his mood will shift into a period
of mania (euphoria)
 between these extremes a period
of normal functioning
 the manic phase can be enjoyable
distressing, disruptive to people`s
life
Manic
Mania is caused by an overproduction of neurotransmitters in the brain.
- lots of energy
- extremely active and talkative
- extremely happy or sometimes extremly angry
- restless and irritable
- racing thoughts - delusions
- unable to sleep much
- voices or see things that aren`t there – hallucinations
- unrealistic beliefs in one's abilities and powers
- abuse of drugs, particularly cocaine, alcohol, sleeping medications
- a lasting period of behavior that is different from usual
A manic episode is diagnosed if elevated mood occurs with three or more
of the symptoms most of the day, nearly every day, for 1week or longer.
Bipolar disorder as a spectrum or
continuous range
 A mild to moderate level of
mania is called hypomania. The
patient shows signs of mania but
doesn`t have delusions or
hallucinations. In a hypomanic
state, the patient may be able to
continue with his life as normal.
 A depressive episode is
diagnosed, if five or more of the
symptoms of depression occur
most of the day, nearly every
day, for a period of 2 weeks or
longer. So the depressive
episodes in BPAD are clinically
identical to depression in the
absence of previous manic
episodes.
Bipolar disorder
 2-3 million people suffer from
bipolar depression (1-2% of the
population)
 genetic factor (15% of children
with one bipolar parent)
 begins during adolescence or
early adulthood
 alcohol and drug abuse or
anxiety disorders
 better controlled if treatment is
continous than if is on and off!
What It's Like Living With Bipolar
Disorder?
Joseph is feeling on top of the world. He has just come off a period where
it was so difficult for him to do anything that he wanted to do. In fact, for a
few months, he didn’t do anything. He just stayed in the house, most of
the time sleeping.
It is certainly different now. In fact, Joseph is almost always out of the
house. He only needs two to three hours sleep a night and he feels that
he has the energy of a bull.
Joseph is spending most of his time on a new project. He is working on a
new business venture that he knows is going to make him a fortune.
Somewhere in the back of his mind he remembers that he has tried to
start new businesses on numerous occasions and they have always
resulted in financial disaster. However, those failures are in the back of
Joseph’s mind now because he knows that this idea is a sure winner.
He is spending most of his days trying to convince banks to lend him the
money. He cannot understand why the banks that he has visited so far
seem so negative, but Joseph is sure that he will find a bank soon that
will advance him the large sum of money that he needs.
He has spared no expense in this effort. Joseph has gone to the best
stores and purchased a new wardrobe. He has ordered the latest in
computer equipment. He also has hired a commercial realtor to find him
modern offices.
Joseph has not told his family about his new idea because they always
rain on his parade. They are negative about all of his ideas. But he
knows that they do not have the vision that he has and that they will eat
their words when they see the millions that he is going to make with his
new venture.
Treatment of bipolar disorders
 medication – mood stabilizers
 supportive psychotherapy
 occasionally ECT
Mood stabilizers are the usual treatment for
bipolar illness. They prevent extreme mood
swings. These drugs must be taken long term
even when the patients feel well.
Mood stabilizers
1.
Lithium- this is the most common treatment and it works
for about 60% of people.
2. Anticonvulsants drugs (such as Carbamazepine(Tegretol),
valproate (Depakote), gabapentin (Neurontin) and
lamotrigine Lamictal), these are given when lithium
doesn`t work or when lithium is unsuitable
Other:
3. antidepressants (such as bupropion (Wellbutrin)or
sertraline (Zoloft)),
4. neuroleptics (e.g. haloperidol)
5. benzodiazepines (e.g. lorazepam)
BPAD is treated with a combination of mood stabilizers,
antipsychotics and antidepressants
Lithium
 Mode of actions – unknown, proposed: mediated
via effects on the IP3 and DAG secondmessenger systems
 Efficacious:
- acute mania
- prophylaxis of classical bipolar disorder
- mania/hypomania-depression
 the onset of action (7-10 days)
 excreted by the kidney
 the high frequency of non-adherence to lithium
treatment (30-50%)
Lithium
 narrow therapeutic range(0.8-1.1 mmols/l)
 necessity of constant monitoring of plasma lithium levels
 heart, kidney, thyroid function
 extremely toxic!
-1.5-2.0 mmol/liter  anorexia, vomiting, diarrhea,
tremor, ataxia, confusion, sleepiness.
- 2.0 mmol/liter  impaired consciousness,
convulsions
 lethal in overdose
 hemodialysis
Adverse effects and toxicity of
lithium








impairment, thirst, nausea
acne, loose stools
tremor
goiter, hypothyroidism
polyuria and polydipsia
edema
weight gain
teratogenic
Drug interactions
Many medications interact adversely with Lithium
1. carbamazepine
2. antipsychotics (haloperidol)
3. cardioactive drugs ( digoxin, angiotensinconverting enzyme inhibitors)
4. diuretics: thiazides and ACE inhibitors
5. nonsteroidal anti-inflammatory drugs
Carbamazepine
antiepileptic drug
reasonable alternative to lithium
used to treat acute mania, mixed state and
also for prophylactic therapy
The mode of action is like of lithium
possible mediated via effects on secondmessenger systems
Carbamazepine used alone or in
combination with lithium.
Carbamazepine

potent inductor of hepatic cytochrome P450
isoenzyme system
 Carbamazepine induces its own
metabolism!
 many drug interactions:
1. Lithium- increases the neurotoxicity of
carbamazepine. The combination of lithium
and carbamazepine -more effective than either
drug alone.
2. Antipsychotics - drowsiness and ataxia
3. TCAs - concentration
4. MAOIs - cheese reaction
Adverse effects of
carbamazepine
 drowsiness,
 diplopia,
 nausea,
 rashes
 headache
 weight gain
 teratogenesis
 hematologic disturbances (agranulocytosis,
leucopenia)
The plasma concentration of carbamazepine
must be monitored!
Valproic acid (valprote)
 an antiepileptic with antimanic effects
 some patients who have failed to respond to
lithium
 Adverse effects:
- gastrointenstinal effects(nausea, vomiting,
diarrhea),
- CNS effects (sedation,tremor)
- hematological effects (thromobocytopenia,
leucopenia)
- Hair loss
 Mode of actions: enhance the syntesis and
release of GABA
Divalproex sodium
 mixture of valproate sodium and valproic
acid
 bioavailability and tolerability
 low drug-drug interaction
 no proven long term risk
 fewer gastrointestinal side effects
Lamotrigine
 an antiepileptic
 well tolerated in bipolar affective disorder
 role in treating the depressive phase of
the illness