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The term "psychosis" denotes a

variety of mental disorders: the
presence of delusions (false beliefs),
various types of hallucinations,
usually auditory or visual, but
sometimes tactile or olfactory, and
grossly disorganized thinking in a
clear sensorium. Schizophrenia is a
particular kind of psychosis
characterized mainly by a clear

The Serotonin Hypothesis of

The discovery that indole hallucinogens such
as LSD (lysergic acid diethylamide) and
mescaline are serotonin (5-HT) agonists led
to the search for endogenous hallucinogens
in the urine, blood, and brains of patients
with schizophrenia. This proved fruitless, but
the identification of many 5-HT-receptor
subtypes led to the pivotal discovery that 5HT2A-receptor stimulation was the basis for
the hallucinatory effects of these agents.

It has been found that 5-HT2A-receptor blockade is

a key factor in the mechanism of action of the
main class of atypical antipsychotic drugs such as
clozapine. These drugs are inverse agonists of the
5-HT2A receptor; that is, they block the constitutive
activity of these receptors. These receptors
modulate the release of dopamine in the cortex,
limbic region, and striatum. Stimulation of 5-HT 2A
receptors leads to depolarization of glutamate
neurons, but also stabilizes NMDA receptors on
postsynaptic NMDA receptors.

The Dopamine Hypothesis of

The dopamine hypothesis for schizophrenia was
the first neurotransmitter-based concept to be
developed but is no longer considered adequate
to explain all aspects of schizophrenia.
Nevertheless, it is still highly relevant to
understanding the major dimensions of
schizophrenia, such as positive and negative
(emotional blunting, social withdrawal, lack of
motivation) symptoms, cognitive impairment, and
possibly depression. It is also essential to
understanding the mechanism of the action of
most and probably all antipsychotic drugs.

Excessive limbic dopaminergic activity plays a

role in psychosis: (1) many antipsychotic drugs
strongly block postsynaptic D2 receptors in the
central nervous system, especially in the
mesolimbic and striatal-frontal system; this
includes partial dopamine agonists, such as
aripiprazole and bifeprunox. (2) Drugs that
increase dopaminergic activity, such as levodopa,
amphetamines, and bromocriptine and
apomorphine, either aggravate schizophrenia
psychosis or produce psychosis de novo in some

The Glutamate Hypothesis of

Glutamate is the major excitatory
neurotransmitter in the brain. Phencyclidine
and ketamine are non competitive inhibitors
of the NMDA receptor that exacerbate both
cognitive impairment and psychosis in
patients with schizophrenia. This was the
starting point for the hypothesis that
hypofunction of NMDA receptors, located on
GABAergic interneurons, leading to diminished
inhibitory influences on neuronal function,
contributed to schizophrenia.

The NMDA receptor, an ion channel, requires

glycine for full activation. It has been
suggested that in patients with schizophrenia,
the glycine site of the NMDA receptor is not
fully saturated. There have been several trials
of high doses of glycine to promote
glutamatergic activity, but the results are far
from convincing. Currently, glycine transport
inhibitors are in development as possible
antipsychotic agents.

Classification of antipsychotic drugs

Main categories are:
first-generation ('typical') antipsychotics
(e.g. chlorpromazine, haloperidol,
fluphenazine, flupenthixol,
second-generation ('atypical')
antipsychotics (e.g. clozapine,
risperidone, sertindole, quetiapine,
amisulpride, aripiprazole, zotepine).

Distinction between typical and

atypical groups is not clearly defined
but rests on:
receptor profile
incidence of extrapyramidal side effects
(less in atypical group)
efficacy (specifically of clozapine) in
'treatment-resistant' group of patients
efficacy against negative symptoms

Dopaminergic Systems
Five important dopaminergic systems
or pathways are present in CNS. The
first pathwaythe one most closely
related to behavior and psychosisis
the mesolimbic-mesocortical
pathway, which projects from cell
bodies near the substantia nigra to
the limbic system and neocortex.


At present, five dopamine receptors
have been described, consisting of
two separate families, the D1-like and
D2-like receptor groups
The D1 type, comprising D1 and D5,
and the D2 type, comprising D2, D3
and D4

Antipsychotic drugs owe their therapeutic

effects mainly to blockade of D 2-receptors.
Antipsychotic effects require about 80%
block of D2-receptors. In animal tests, all
antipsychotic drugs initially increase and
later decrease the electrical activity of
midbrain dopaminergic neurons in the
substantia nigra and ventral tegmentum,
and also the release of dopamine in regions
containing dopaminergic nerve terminals

These changes are possibly

associated with changes in dopamine
receptor expression.
Effects on the
mesolimbic/mesocortical dopamine
pathways are believed to correlate
with antipsychotic effects, whereas
effects on the nigrostriatal pathways
are responsible for the unwanted
motor effects produced by

Chlorpromazine, Fluphenazine, Thioridazine
Thioxanthene Derivatives
Butyrophenone Derivatives
This group, of which haloperidol is the most
widely used, has a very different structure
from those of the two preceding groups.
Haloperidol, a butyrophenone, is the most
widely used typical antipsychotic drug

Atypical Antipsychotic Drugs

Loxapine, clozapine, asenapine,
olanzapine, quetiapine,
paliperidone, risperidone,
sertindole, ziprasidone,
zotepine, and aripiprazole are
atypical antipsychotic drugs.
Clozapine is the prototype.

Most antipsychotic drugs are readily but incompletely
absorbed. Furthermore, many undergo significant firstpass metabolism. Thus, oral doses of chlorpromazine and
thioridazine have systemic availability of 2535%,
whereas haloperidol, which has less first-pass metabolism,
has an average systemic availability of about 65%.
Most antipsychotic drugs are highly lipid-soluble and
protein-bound (9299%). They tend to have large volumes
of distribution (usually more than 7 L/kg). They generally
have a much longer clinical duration of action than would
be estimated from their plasma half-lives. This is
paralleled by prolonged occupancy of D2 dopamine
receptors in the brain by the typical antipsychotic drugs.

Clinical uses of
antipsychotic drugs
Behavioural emergencies (e.g. violent
patients with a range of
psychopathologies including mania,
toxic delirium and schizophrenia
classic antipsychotic drugs (e.g.
chlorpromazine, haloperidol) can rapidly
control hyperactive psychotic states
note that the intramuscular dose is lower
than the oral dose of the same drug
because of presystemic metabolism.

Many chronic schizophrenic patients are
treated with first generation
antipsychotic drugs. Depot injections
(e.g. flupentixol decanoate) may be
useful for maintenance treatment when
compliance with oral treatment is a
problem. Flupentixol has
antidepressant properties distinct from
its antipsychotic action.

Atypical antipsychotic drugs (e.g.

amisulpride, olanzapine,
risperidone) are used if
extrapyramidal symptoms are
troublesome, if symptom control is
inadequate, or for newly diagnosed

Clozapine can cause agranocytosis

but is distinctively effective against
'negative' features of schizophrenia.
It is reserved for patients whose
condition remains inadequately
controlled despite previous use of
two or more antipsychotic drugs, of
which at least one is atypical. Blood
count is monitored weekly for the
first 18 weeks, and less frequently

Unwanted effects of antipsychotic

Important side effects common to most drugs are
extrapyramidal motor disturbances (see Antipsychoticinduced motor disturbances box) and endocrine
disturbances (increased prolactin release); these are
secondary to dopamine receptor block. Sedation,
hypotension and weight gain are also common.
Obstructive jaundice sometimes occurs with
Other side effects (dry mouth, blurred vision,
hypotension, etc.) are due to block of other receptors,
particularly -adrenoceptors and muscarinic
acetylcholine receptors.

Some antipsychotic drugs cause

agranulocytosis as a rare and serious
idiosyncratic reaction. With
clozapine, leucopenia is common and
requires routine monitoring.
Antipsychotic malignant syndrome is
a rare but potentially dangerous
idiosyncratic reaction.

Antipsychotic-induced motor
Major problem of antipsychotic drug
Two main types of disturbance occur:
acute, reversible dystonias and
Parkinson-like symptoms
slowly developing tardive dyskinesia,
often irreversible.

Acute symptoms comprise involuntary

movements, tremor and rigidity, and are
probably the direct consequence of block of
nigrostriatal dopamine receptors.
Tardive dyskinesia comprises mainly
involuntary movements of face and limbs,
appearing after months or years of
antipsychotic treatment. It may be associated
with proliferation of dopamine receptors
(possibly presynaptic) in corpus striatum.
Treatment is generally unsuccessful.

Incidence of acute dystonias and

tardive dyskinesia is less with
atypical antipsychotics, and
particularly low with clozapine,
aripiprazole and zotepine. This may
reflect relatively strong muscarinic
receptor block with these drugs, or a
degree of selectivity for the
mesolimbic, as opposed to the
nigrostriatal, dopamine pathways.

Lithium, Mood-Stabilizing Drugs, and

Other Treatment for Bipolar Disorder
Lithium was the first agent shown to
be useful in the treatment of the
manic phase of bipolar disorder that
was not also an antipsychotic drug.
Lithium has no known use in
schizophrenia. Lithium continues to
be used for acute-phase illness as
well as for prevention of recurrent
manic and depressive episodes.

Another group of mood-stabilizing drugs that

are also anticonvulsant agents have become
more widely used than lithium. These include
carbamazepine and valproic acid for the
treatment of acute mania and for prevention
of its recurrence. Lamotrigine is approved
for prevention of recurrence. Gabapentin,
oxcarbazepine, and topiramate are
sometimes used to treat bipolar disorder but
are not approved by FDA for this indication.

Aripiprazole, chlorpromazine,
olanzapine, quetiapine,
risperidone, and ziprasidone are
approved by FDA for the treatment of
manic phase of bipolar disorder.
Olanzapine plus fluoxetine in
combination and quetiapine are
approved for the treatment of bipolar

Lithium directly inhibits two signal

transduction pathways. It both
suppresses inositol signaling through
depletion of intracellular inositol and
inhibits glycogen synthase kinase-3
(GSK-3), a multifunctional protein
kinase. GSK-3 is a component of
diverse intracellular signaling

inositol trisphosphate and diacylglycerol are

important second messengers for both -adrenergic
and muscarinic transmission. Lithium inhibits
inositol monophosphatase and other important
enzymes in the normal recycling of membrane
phosphoinositides, including conversion of IP2
(inositol diphosphate) to IP1 (inositol
monophosphate) and the conversion of IP1 to
inositol . This block leads to a depletion of free
inositol and ultimately of phosphatidylinositol-4,5bisphosphate (PIP2), the membrane precursor of IP3
and DAG.

Over time, the effects of transmitters

on the cell diminish in proportion to
the amount of activity in the PIP2dependent pathways. The activity of
these pathways is postulated to be
markedly increased during a manic
episode. Treatment with lithium
would be expected to diminish the
activity in these circuits

lithium carbonate was the universally

preferred treatment for bipolar
disorder, especially in the manic
phase. With the approval of
valproate, aripiprazole, olanzapine,
quetiapine, risperidone, and
ziprasidone for this indication, a
smaller percentage of bipolar
patients now receive lithium.

Side Effects
Tremor is one of the most common adverse
effects of lithium treatment, and it occurs
with therapeutic doses. Propranolol and
atenolol, which have been reported to be
effective in essential tremor, also alleviate
lithium-induced tremor.
Lithium probably decreases thyroid function
in most patients exposed to the drug, but
the effect is reversible or nonprogressive.

Polydipsia and polyuria are common

but reversible concomitants of
lithium treatment, occurring at
therapeutic serum concentrations.
The principal physiologic lesion
involved is loss of responsiveness to
antidiuretic hormone (nephrogenic
diabetes insipidus). Lithium-induced
diabetes insipidus is resistant to
vasopressin but responds to

Edema is a common adverse effect

of lithium treatment and may be
related to some effect of lithium on
sodium retention.
The bradycardia-tachycardia ("sick
sinus") syndrome is a definite
contraindication to the use of lithium
because the ion further depresses
the sinus node.

Newer agents for bipolar

Carbamazepine, Lamotrigine, Valproic
Mechanism of action in bipolar
disorder unclear
Valproic acid is increasingly used as
first choice in acute illness
carbamazepine and lamotrigine are
also used both in acute mania and
for prophylaxis in depressive phase

Carbamazepine causes dose-related diplopia and

ataxia lamotrigine causes nausea, dizziness, and
headache valproic acid causes gastrointestinal
distress, possible weight gain, alopecia
Oral absorption once-daily dosing carbamazepine
forms active metabolite lamotrigine and valproic
acid form conjugates Toxicity: Hematotoxicity and
induction of P450 drug metabolism
(carbamazepine), rash (lamotrigine), tremor, liver
dysfunction, weight gain, inhibition of drug
metabolism (valproic acid)