pharmacology

1. Antipsychotic Agents & Lithium

2. Antipsychotic Agents
• The terms antipsychotic & neuroleptic are used to denote a
group of drugs that have been used mainly for treating
schizophrenia but are also effective in some other psychoses
and agitated states.
• Nature of Psychosis & Schizophrenia
• The term "psychosis" denotes a variety of mental disorders.
Schizophrenia is a particular kind of psychosis characterized
mainly by marked thinking disturbance.
• The pathogenesis of schizophrenia is unknown. Largely as a
result of research stimulated by the discovery of antipsychotic
drugs, a genetic predisposition has been proposed as a
necessary but not always sufficient condition underlying
psychotic disorder.

3. • Basic Pharmacology of Antipsychotic Agents
• The Dopamine Hypothesis
• The dopamine hypothesis for schizophrenia is the most
fully developed of several hypotheses and is the basis for
much of the rationale for drug therapy. Several lines of
circumstantial evidence suggest that excessive
dopaminergic activity plays a role in the disorder:
(1) most antipsychotic drugs strongly block postsynaptic D2
receptors in the CNS esp.in the mesolimbic-frontal system.
(2) drugs that increase dopaminergic activity, such as
levodopa (a precursor), amphetamines (releasers of
dopamine) or apomorphine (dopamine agonist), either
aggravate schizophrenia or produce psychosis.

4. BASIC PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS
• Chemical Types
• A number of chemical structures have been associated with
antipsychotic properties.
A. PHENOTHIAZINE DERIVATIVES
• Three subfamilies of phenothiazines, were the most widely
used of the antipsychotics.
• Aliphatic derivatives (eg, chlorpromazine) and piperidine
derivatives (eg, thioridazine).
• Piperazine derivatives are more potent but not necessarily
more efficacious. The piperazine derivatives are also more
selective in their pharmacologic effects.

5. B. THIOXANTHENE DERIVATIVES
• This group of drugs is exemplified primarily by thiothixene
C. BUTYROPHENONE DERIVATIVES
• Haloperidol is the most widely used, has a very different
structure from those of the two preceding groups.
• The butyrophenones and congeners tend to be more
potent and to have fewer autonomic effects but greater
extrapyramidal effects.
D. MISCELLANEOUS STRUCTURES
• The newer drugs, have a variety of structures and include
pimozide, loxapine, clozapine, olanzapine, quetiapine,
risperidone, ziprasidone and aripiprazole

6. • Pharmacokinetics
• Most antipsychotics are readily but incompletely absorbed.
Many of them undergo significant first-pass metabolism.
• Most antipsychotics are highly lipid-soluble and protein-
bound. They tend to have large volumes of distribution.
• Because of lipid solubility, they readily enter CNS and have
a high affinity for dopamine receptors, they have a much
longer clinical duration of action. This is paralleled by
prolonged occupancy of dopamine D2 receptors in brain.
• Metabolites of chlorpromazine is excreted in the urine
weeks after the last dose of chronically administered drug.
• Similarly, full relapse may not occur until 6 weeks or more
after discontinuation of many antipsychotic drugs.

7. B. METABOLISM
• Most antipsychotic drugs are almost completely
metabolized. Although some metabolites retain activity,
eg, 7-hydroxychlorpromazine.
• The sole exception is mesoridazine, the major metabolite
of thioridazine, which is more potent than the parent
compound and accounts for most of the effect.
• Very little of these antipsychotic drugs is excreted
unchanged, because they are almost completely
metabolized to more polar substances.

8. • Pharmacologic Effects
• Phenothiazine antipsychotic drugs, with chlorpromazine as
the prototype, proved to have a wide variety of CNS,
autonomic and endocrine effects. These actions were
traced to blocking effects at a wide range of receptors,
including dopamine, α-adrenoceptor, muscarinic, H1-
histaminic, and serotonin (5-HT2) receptors.
A. DOPAMINERGIC SYSTEMS
• Five important dopaminergic systems or pathways are now
recognized in the brain. The first pathway, the one most
closely related to behavior is the mesolimbic-mesocortical
pathway.

9. • The second system, the nigrostriatal pathway. It is
involved in the coordination of voluntary movement.
• The third pathway, the tuberoinfundibular system.
Dopamine released by these neurons physiologically
inhibits prolactin secretion.
• The fourth dopaminergic system- the medullary-
periventricular pathway. This system may be involved in
eating behavior.
• The fifth pathway- the incerto-hypothalamic pathway.
It appears to regulate the anticipatory motivational
phase of copulatory behavior in rats.

10. • The antipsychotic action is now thought to be produced by
their ability to block dopamine in the mesolimbic and
mesocortical systems.
• Furthermore, the antagonism of dopamine in the
nigrostriatal system explains the unwanted effect of
parkinsonism like side effect produced by these drugs.
• The hyperprolactinemia that follows treatment with
antipsychotics is caused by blockade of dopamine's tonic
inhibitory effect on prolactin release from the pituitary.

11. B. DOPAMINE RECEPTORS AND THEIR EFFECTS
• Five dopamine receptors have been described, consisting
of two families, the D1-like and D2-like receptor groups.
• The D1 and D5 receptors increase cAMP by Gs-coupled
activation of adenylyl cyclase.
• The D2, D3 and D4 receptor decreases cAMP (by Gi-
coupled inhibition of adenylyl cyclase), and inhibits calcium
channels but opens potassium channels.
• The therapeutic potency of antipsychotic drugs does not
correlate with their affinity for binding the D1 receptor but
correlates strongly with D2 affinity.

12. • The activation of D2 receptors by direct or indirect
agonists (amphetamines, levodopa, apomorphine) causes
increased motor activity and stereotyped behavior in rats,
a model that is used for antipsychotic drug screening.
• In humans, the same drugs aggravate schizophrenia.
• The antipsychotic agents block D2 receptors and their
binding affinity is very strongly correlated with clinical
antipsychotic and extrapyramidal potency.

13. • Newer drugs, clozapine, olanzapine, quetiapine &
aripiprazole do not have very high affinity for the D2
receptor, which suggests that additional actions to their
antipsychotic effects.
• Most of the newer "atypical" antipsychotic agents and some
of the traditional ones have significant affinity for the 5-
HT2A receptor, suggesting an important role for the
serotonin system.
• Participation of glutamate, GABA, and acetylcholine receptors
in the pathophysiology of schizophrenia has also been
proposed.

14. C. DIFFERENCES AMONG ANTIPSYCHOTIC DRUGS
• Although all effective antipsychotic drugs block D2
receptors, the degree of this blockade in relation to other
actions on receptors varies between drugs:
Chlorpromazine: α1 = 5-HT2A >D2 > D1
Haloperidol: D2 > α1> D4 > 5-HT2A > D1 > H1
Clozapine: D4 = α1> 5-HT2A > D2 = D1
Olanzapine: 5-HT2A > H1 > D4 > D2 > α 1 > D1
Aripiprazole: D2 = 5-HT2A > D4 > α 1 = H1 >> D1
Quetiapine: H1 > α 1 > M1,3 > D2 > 5-HT2A
• Thus, most of the atypical antipsychotic agents are at least
as potent in inhibiting 5-HT2 receptors as they are in
inhibiting D2 receptors.

15. • The newest, aripiprazole, appears to be a partial agonist of
D2 receptors.
• Current research is directed toward discovering atypical
antipsychotic compounds that are more selective for the
mesolimbic system (reduce their extrapyramidal effects) or
have effects on central neurotransmitter receptors such as
acetylcholine and glutamate that have been proposed as
new targets for antipsychotic action.
• These differences in the receptor effects of various
antipsychotics explain many of their toxicities. In
particular, extrapyramidal toxicity appears to be associated
with high D2 potency.

16. D. PSYCHOLOGICAL EFFECTS
• Most antipsychotic drugs cause unpleasant subjective
effects in nonpsychotic individuals; sleepiness, restlessness
and impaired performance. Psychotic individuals, however,
may actually show improvement in their performance as
the psychosis is alleviated.
E. ELECTROENCEPHALOGRAPHIC EFFECTS
• Antipsychotic drugs produce shifts in the pattern of EEG,
usually slowing them and increasing their synchronization
is sometimes focal or unilateral. Some neuroleptics lower
the seizure threshold and induce EEG patterns typical of
seizure disorders; however, with careful dosage, most can
be used safely in epileptic patients.

17. F. ENDOCRINE EFFECTS
• Older antipsychotics produce adverse effects on the
reproductive system. Amenorrhea, galactorrhea and
infertility, gynecomastia and decreased libido.
• Some of these effects are secondary to blockade of
dopamine's tonic inhibition of prolactin secretion; others
may be due to increased peripheral conversion of
androgens to estrogens.
• Newer antipsychotics eg olanzapine, quetiapine and
aripiprazole have no or minimal increases of prolactin and
reduced risks of extrapyramidal dysfunction and tardive
dyskinesia as well as endocrine dysfunction.

18. G. CARDIOVASCULAR EFFECTS
• Orthostatic hypotension result from use of phenothiazines.
These effects are from the autonomic actions of these
agents (α- adrenergic blocking action).
• Abnormal ECGs have been recorded, especially with
thioridazine. Changes include prolongation of QT interval &
abnormal configurations of the ST segment and T waves.
• Among the newest antipsychotics, prolongation of the QT or
QTc interval with increased risk of arrhythmias has been of
such concern that the atypical drug Ziprasidone.

19. CLINICAL PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS
• Indications
A. PSYCHIATRIC INDICATIONS
• Schizophrenia is the primary indication for antipsychotic agents,
which remain the mainstay of treatment for this condition.
Unfortunately, many patients show little or response.
• Antipsychotics are also indicated for disorders, which share
characteristics of both schizophrenia and affective disorders.
• The psychotic aspects of the illness require treatment with
antipsychotic drugs, which may be used with other drugs such
as antidepressants, lithium, or valproic acid.
• The manic phase in bipolar affective disorder requires
treatment with antipsychotic agents, while lithium or valproic
acid supplemented with BZD (lorazepam or clonazepam) may
be sufficient in milder cases.

20. • Recent trials support the efficacy of monotherapy with
atypical antipsychotics in the acute phase of mania and
olanzapine has been approved for this indication.
• As mania subsides, the antipsychotic drug may be
withdrawn, although maintenance treatment with atypical
antipsychotics has become more common.
• Other indications for the use of antipsychotics include
Tourette's syndrome, disturbed behavior in patients with
Alzheimer's disease.

21. B. NONPSYCHIATRIC INDICATIONS
• Most older antipsychotic drugs, with the exception of
thioridazine, have a strong antiemetic effect. This action is
due to dopamine receptor blockade, both centrally (in the
CTZ of the medulla) and peripherally (in the stomach). Some
drugs, such as prochlorperazine is used as antiemetics.
• Phenothiazines with shorter side chains have considerable
H1-receptor-blocking action and have been used for relief of
pruritus or, in the case of promethazine, as preoperative
sedatives.
• The butyrophenone droperidol is used in combination with
an opioid, fentanyl, in neuroleptanesthesia.

22. • Drug Choice
• Choice among antipsychotic drugs is based mainly on
differences in adverse effects and in efficacy.
• Since use of the older drugs is still widespread, such
agents as chlorpromazine and haloperidol.
• Thus, one should be familiar with one member of each of
the subfamilies of phenothiazines, a member of the
thioxanthine and butyrophenone group, and all of the
newer compounds; clozapine, risperidone, olanzapine,
quetiapine, ziprasidone and aripiprazole.

23. • New antipsychotic drugs are more effective than older
ones for treating negative symptoms (emotional blunting,
social withdrawal, lack of motivation).
• The illness accompanied by uncontrollable behavior is still
frequently treated with older drugs.
• The low cost of the older drugs contributes to their
widespread use despite their disadvantages including
extrapyramidal side effects and hyperprolactinemia.
• Newer antipsychotics; clozapine, risperidone and
olanzapine, are superior over haloperidol.
• The superior side-effect of the newer agents and no risk of
tardive dyskinesia suggest that these should provide the
first line of treatment.

24. • The best guide for selecting a drug for an individual patient
is the patient's past responses to drugs.
• Within the older group, the trend has been away from low-
potency agents such as chlorpromazine and thioridazine
toward the high-potency drugs such as haloperidol.
• At present, clozapine is limited to those patients who have
failed to respond to conventional antipsychotics due to the
risk of agranulocytosis.
• Risperidone has less side-effect (compared with haloperidol)
the lower risk of tardive dyskinesia have contributed to its
widespread use. Olanzapine and quetiapine may have even
lower risk and have achieved widespread use.

25. • Maintenance Treatment
• A very small minority of schizophrenic patients may recover
from an acute episode and require no further drug therapy
for prolonged periods.
• In most cases, the choice is between "as needed" increased
doses or addition of other drugs for exacerbations versus
continual maintenance treatment with full therapeutic doses.
• The choice depends on the availability of family or friends
familiar with the symptoms of early relapse.

26. • Drug Combinations
• Combining antipsychotics confuses evaluation of the efficacy
of the drugs being used. Use of combinations, however, is
widespread.
• Tricyclic antidepressants or selective serotonin reuptake
inhibitors may be used with antipsychotics to clear symptoms
of depression complicating schizophrenia.
• Lithium or valproic A is added to antipsychotics with benefit
to patients who do not respond to antipsychotics alone.
• Sedative drugs may be added for relief of anxiety or
insomnia not controlled by antipsychotics.

27. • Adverse Reactions
A. BEHAVIORAL EFFECTS
• Older antipsychotics are unpleasant to take. Many patients
stop taking them because of the adverse effects, which
may be lessened by giving small doses during the day and
the major portion at bedtime.
• A "pseudodepression" that may be due to drug-induced
akinesia usually responds to treatment with
antiparkinsonism drugs. Other pseudodepressions may be
due to higher doses, decreasing the dose may relieve the
symptoms in these cases.
• Toxic-confusional states may occur with very high doses of
drugs that have prominent antimuscarinic actions.

28. B. NEUROLOGIC EFFECTS
• Extrapyramidal reactions occurring early during treatment
with older agents include typical Parkinson's syndrome,
akathisia (restlessness) and acute dystonic reactions
(retrocollis or torticollis).
• Parkinsonism can be treated with conventional
antiparkinsonism drugs (antimuscarinic type, Levodopa
should never be used in these patients). Parkinsonism may
be self-limiting, so that an attempt to withdraw
antiparkinsonism drugs should be made every 3-4 months.
• Akathisia and dystonic reactions also respond to
antiparkinsonism drug, but many prefer to use antihistamine
with anticholinergic properties, eg, diphenhydramine, which
can be given either parenterally or orally.

29. • Tardive dyskinesia is a late-syndrome, is the most important
side effect of antipsychotics. It has proposed that it is caused
by a relative cholinergic deficiency secondary to
supersensitivity of dopamine receptors.
• Early recognition is important, since advanced cases may be
difficult to reverse. The first step of treatment is to
discontinue or reduce the dose of the current antipsychotic
or switch to one of the newer atypical agents.
• A second step would be to eliminate all drugs with central
anticholinergic action, particularly antiparkinsonism drugs
and tricyclic antidepressants.
• These two steps are often enough to bring about
improvement. If they fail, the addition of diazepam may add
to the improvement by enhancing GABAergic activity.

30. • Seizures, is a complication of chlorpromazine, it is rare with
the high-potency older drugs. However, de novo seizures
may occur in 2-5% of patients treated with clozapine.
C. AUTONOMIC NERVOUS SYSTEM EFFECTS
• Most patients can tolerate the antimuscarinic adverse effects
of antipsychotics. Those who develop severe symptoms
(urinary retension) can switched to agents with little
antimuscarinic action.
• Orthostatic hypotension or impaired ejaculation; is common
complications with chlorpromazine, should be managed by
switching to drugs with less α-adrenoceptor-blocking actions.
D. METABOLIC AND ENDOCRINE EFFECTS
• Weight gain is very common, especially with clozapine and
olanzapine, and requires monitoring of food intake.

31. • Hyperglycemia may develop, secondary to weight gain-
associated insulin resistance. Hyperprolactinemia in women
results in the amenorrhea-galactorrhea syndrome and
infertility; in men, loss of libido, impotence, and infertility.
E. TOXIC OR ALLERGIC REACTIONS
• Agranulocytosis, cholestatic jaundice and skin eruptions
occur rarely with the high-potency antipsychotics.
• Clozapine causes agranulocytosis in ~ 1-2% patients. This
serious, fatal effect develop rapidly, usually between the 6th
& 18th weeks of therapy. It appears to be reversible upon
discontinuance of the drug.
• Because of the risk of agranulocytosis, patients receiving
clozapine must have weekly blood counts for the first 6
months of treatment and every 3 weeks thereafter.

32. F. OCULAR COMPLICATIONS
• Deposits in the cornea and lens are a common complication
of chlorpromazine.
• Thioridazine is the only antipsychotic that causes retinal
deposits, which may resemble retinitis pigmentosa. The
deposits are usually associated with "browning" of vision.
G. CARDIAC TOXICITY
• Thioridazine is almost always associated with minor
abnormalities of T-waves that are easily reversible.
• Overdoses of thioridazine are associated with major
ventricular arrhythmias, cardiac conduction block and sudden
death. Ziprasidone carries the greatest risk of QT
prolongation and should not be combined with drugs that
prolong the QT interval; thioridazine, pimozide & quinidine.

33. H. USE IN PREGNANCY; DYSMORPHOGENESIS
• Although the antipsychotics appear to be relatively safe in
pregnancy, a small increase in teratogenic risk could be
missed.
I. NEUROLEPTIC MALIGNANT SYNDROME
• This life-threatening disorder occurs in patients who are
sensitive to the extrapyramidal effects of antipsychotics.
The initial symptom is marked muscle rigidity.
• Leukocytosis and high fever associated with this syndrome
may wrongly suggest an infectious process. Autonomic
instability, with altered blood pressure and pulse rate, is
often present. Creatine kinases are usually elevated,
reflecting muscle damage.

34. • This syndrome is believed to result from an excessively
rapid blockade of postsynaptic dopamine receptors. A
severe form of extrapyramidal syndrome follows.
• Early in the course, treatment of the extrapyramidal
syndrome with antiparkinsonism drugs is useful.
• Muscle relaxants, particularly diazepam, are often useful.
Other muscle relaxants, such as dantrolene, or dopamine
agonists, as bromocriptine, have been reported to be
helpful. If fever is present, cooling by physical measures
should be tried.

35. • Drug Interactions
• Antipsychotics produce more important pharmacodynamic
than pharmacokinetic interactions because of their multiple
effects. Additive effects may occur when they are combined
with e.g., sedative, α-adrenoceptor-blocker, anticholinergics
and for thioridazine and ziprasidone-quinidine-like action.

36. • Lithium & Other Mood-Stabilizing Drugs
• Lithium carbonate is often referred to as an "antimanic"
drug, and "mood-stabilizing" agent because of its primary
action of preventing mood swings in patients with bipolar
affective (manic-depressive) disorder.
• Carbamazepine has also been recognized as effective in
some groups of manic-depressive patients despite not being
formally approved for such use.
• Valproate has recently been approved for the treatment of
mania and is being evaluated as a mood stabilizer.
• Atypical antipsychotics, olanzapine, are being investigated
and approved as antimanic agents and potential mood
stabilizers.

37. Basic Pharmacology of Lithium
• Pharmacokinetics
• Lithium is a small monovalent cation. Its pharmacokinetics
are summarized in Table 29–5.

38. • Pharmacodynamics
• Despite considerable investigation, the mode of action of
lithium remains unclear. The major possibilities include (1)
effects on electrolytes and ion transport; (2) effects on
neurotransmitters and their release; and (3) effects on
second messengers and intracellular enzymes that mediate
transmitter action. The last of these three approaches
appears to be the most promising.
1. Effects on Electrolytes and Ion Transport
• Lithium is closely related to sodium in its properties. It can
substitute for sodium in generating action potentials and in
Li+ - Na + exchange across the membrane. It inhibits the
latter process, ie, Li+ - Na+ exchange is gradually slowed
after lithium is introduced into the body.

39. • Effects on Neurotransmitters
• Lithium appears to enhance some of the actions of
serotonin. Its effects on norepinephrine are variable.
• The drug may decrease norepinephrine and dopamine
turnover, and these effects, if confirmed, might be relevant
to its antimanic action.
• Lithium also appears to block the development of dopamine
receptor supersensitivity that may accompany chronic
therapy with antipsychotic agents.
• Finally, lithium may augment the synthesis of acetylcholine,
perhaps by increasing choline uptake into nerve terminals.
• Some clinical studies have suggested that increasing
cholinergic activity may alleviate mania.

40. • Effects on Second Messengers
• One of the best-defined effects of lithium is its action on
inositol phosphates.
• Lithium changes in brain inositol phosphate levels, but the
significance of these changes was not appreciated until the
second-messenger roles of inositol-1,4,5-trisphosphate (IP3)
and diacylglycerol (DAG).
• Lithium inhibits several important enzymes in the normal
recycling of membrane phosphoinositides; conversion of IP2
to IP1 (inositol monophosphate) and the conversion of IP to
inositol (Figure 29–4).

41. • This block leads to a depletion of phosphatidylinositol-4,5-
bisphosphate (PIP2), the membrane precursor of IP3 and DAG.

42. Clinical Pharmacology of Lithium
• Bipolar Affective Disorder
• Until recently, lithium was the universally preferred
treatment for bipolar disorder, especially in the manic
phase. With the approval of valproate and olanzapine for
this indication, a smaller fraction of bipolar patients now
receive lithium.
• Recent controlled trials, the anticonvulsant lamotrigine is
effective for many patients with bipolar depression.
• Antipsychotic drugs alone or combined with lithium are
used in the the maintenance phases; clozapine may be
effective. Various antidepressants are added if depression
is present.

43. • Drug Interactions
• Renal clearance of lithium is reduced about 25% by
diuretics (eg, thiazides), and doses may need to be
reduced by a similar amount.
• A similar reduction in lithium clearance has been noted
with several of the newer NSAIDs drugs that block
synthesis of prostaglandins. This interaction has not been
reported for either aspirin or acetaminophen.
• All neuroleptics tested to date, with the possible exception
of clozapine and the newer antipsychotics, may produce
more severe extrapyramidal syndromes when combined
with lithium.

44. • Adverse Effects & Complications
Many adverse effects associated with lithium treatment
occur at varying times after treatment is started.
1. Neurologic and Psychiatric Adverse Effects
• Tremor is one of the most frequent adverse effects of
lithium treatment, occurring at therapeutic dosage levels.
• Propranolol and atenolol, which have been reported to be
effective in lithium-induced tremor.
• Other neurologic abnormalities include choreoathetosis,
motor hyperactivity, ataxia, dysarthria and aphasia.
• Psychiatric disturbances at toxic conc are generally marked
by mental confusion and withdrawal or bizarre motor
movements.

45. • Effects on Thyroid Function
• Lithium probably decreases thyroid function in most patients,
but the effect is reversible or nonprogressive. Few patients
develop thyroid enlargement and fewer still show symptoms of
hypothyroidism. Although initial thyroid testing followed by
regular monitoring of thyroid function has been proposed, such
procedures are not cost-effective. Obtaining a serum TSH
concentration every 6–12 months, however, is cautious.
• Renal Adverse Effects
• Polydipsia and polyuria are frequent but reversible
concomitants of lithium treatment, occurring at therapeutic
serum conc. The principal physiologic lesion involved is loss of
the ability of the collecting tubule to conserve water under the
influence of antidiuretic hormone, resulting in (nephrogenic
diabetes insipidus).

46. • Lithium-induced diabetes insipidus is resistant to
vasopressin but responds to amiloride.
• Other renal dysfunction during longterm lithium
therapy, including chronic interstitial nephritis and
glomerulopathy with nephrotic syndrome.
• Patients receiving lithium should avoid dehydration and
the associated increased concentration of lithium in urine.
Periodic tests of renal concentrating ability should be
performed to detect changes.

47. • Edema
• Edema is a frequent adverse effect of lithium & may be
related to some effect of lithium on Na+ retention. Weight
gain may be observed in up to 30% of patients taking
lithium.
• Cardiac Adverse Effects
• The bradycardia-tachycardia ("sick sinus") syndrome is a
definite contraindication to the use of lithium because the
ion further depresses the sinus node. T-wave flattening is
often observed on the ECG but is of questionable
significance.
• Use during Pregnancy
• Renal clearance of lithium increases during pregnancy and
reverts to lower levels immediately after delivery.

48. • Miscellaneous Adverse Effects
• Transient acneiform eruptions have been noted early in
lithium treatment. Some of them subside with temporary
discontinuance of treatment and do not recur with its
resumption.
• Leukocytosis is always present during lithium treatment,
probably reflecting a direct effect on leukopoiesis rather than
mobilization from the marginal pool. This "adverse effect"
has now become a therapeutic effect in patients with low
leukocyte counts.

49. • Valproic Acid
• Valproate is an antiseizure Drugs, has been demonstrated to
have antimanic effects & now widely used for this indication.
• It shows efficacy equivalent to that of lithium during the
early weeks of treatment. Valproic has been effective in
some patients who have failed to respond to lithium..
• Combinations of valproic acid with other psychotropic
medications likely to be used in the management of either
phase of bipolar illness are generally well tolerated.
• Valproic A is recognized as a first-line treatment for mania,
though it is not clear that it will be as effective as lithium as
a maintenance treatment in all patients. Many clinicians
argue for combining valproic and lithium in patients who do
not fully respond to either agent alone.

50. • Carbamazepine
• Carbamazepine has been considered to be an alternative to
lithium when the latter is less efficacious. It may be used to
treat acute mania and also for prophylactic therapy.
Carbamazepine may be used alone or, in refractory patients,
in combination with lithium or, rarely, valproate.
• The mode of action of carbamazepine is unclear.
• Adverse effects are generally less than those associated with
lithium. Blood dyscrasias are prominent adverse effects of
carbamazepine, they have not been a major problem when
uses as a mood stabilizer.
• Overdoses of the drug are a major emergency and should be
managed in general like overdoses of tricyclic
antidepressants.