Introduction to psychoses, schizophrenia and various approaches to its management and treatment. Along with pharmacology and ADR.

2. CONTENTS
PSYCHOSES
SCHIZOPHRENIA
RELATED THEORIES.
CLASSIFICATION OF ANTI-PSYCHOTIC AGENTS.
CHLORPROMAZINE(PROTOTYPE)
MECHANISM OF ACTION.
PHARMACOLOGICAL ACTIONS.
PHARMACOKINETICS.
ADVERSE DRUG REACTIONS.
OTHER ANTIPSYCHOTIC AGENTS.
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3. PSYCHOSES
• “severe psychiatric illness with serious distortion of
thought, behavior, capacity to recognize reality & of
perception (delusions & hallucinations)”.
• A hallucination is an internal sensory perception that
isn’t actually present and can be either visual or
auditory. Smelling odours or having a funny taste in
month.
• A delusion is defined as a false, inaccurate belief that
a person holds on to. A grandiose delusion occurs
when a person believes that their life is out of
proportion as compared to what is really true. For
example, a patient may believe that she is the Queen
of England.
• A persecutory delusion occurs when a person
believes that there is a conspiracy amongst others to
attack, punish or harass him. Although these
hallucinations and delusions appear odd to others,
they are very real to the person with the disorder.
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4. SCHIZOPHRENIA
“Schizophrenia is a mental disorder characterized by a disintegration of thought
processes and of emotional responsiveness. It most commonly manifests as
auditory hallucinations, bizarre delusions, or disorganized speech and thinking, and
it is accompanied by significant social or occupational dysfunction.”
• Schizophrenia commonly starts at an early age ( late teenage – 20s)
• Strong hereditary tendency.
• Schizo(split) phrenia(mind)
Positive Symptoms Negative Symptoms Cognitive
Disturbance of perception
(hallucinations),
disturbance of thought
content (delusions),
disorganization of thought,
speech, & behavior
Decreased expression of
feelings, diminished
emotional range, poverty of
speech, decreased interests
& diminished sense of
purpose & social drive
Poor concentration,
memory disturbances,
inability to plan, difficulty
executing task, impaired
decision making
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5. TREATMENT
• The two main forms of treatment for
psychotic disorders are medication and
psychotherapy. The medications to treat
psychotic disorders are antipsychotics.
These medications aid in managing the
symptoms of the disease like the
hallucinations and delusions.
• Psychotherapy for psychotic disorders may
include individual sessions, family sessions
and support groups. While most patients
are treated as outpatients, in severe cases,
such as when the physical well-being is in
danger, hospitalization may be necessary to
stabilize the patient’s condition. 5

6. Dopamine Theory of Schizophrenia
 Dopamine theory was proposed by
Carlson based on indirect evidences.
Drugs which increase DA activity
(amphetamines, Ievodopa,
bromocriptine) induce or exacerbate
schizophrenia, This has given rise to the
'Dopamine theory of Schizophrenia‘
stating DA overactivity in limbic area to
be responsible for the condition.
Drugs that reduce dopaminergic activity (
DA antagonists like chlorpromazine, DA
storage depletor- reserpine) controls
symptoms of schizophrenia and also
prevent amphetamine induced
behavioural changes. 6

7. Glutamate Theory
NMDA receptor antagonists like ketamine and phencyclidine produce
symptoms of psychoses.(they cause dopamine release in cortex and
striatum)
As per post-mortem findings there is a decrease in glutamate
concentration and glutamate receptor density in brain of schizophrenic
patients.
Deficient NMDA receptor activity is the cause of negative symptoms,
DA overactivity is responsible for positive symptoms.
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8. ANTIPSYCHOTIC AGENTS
Phenothiazine derivatives:
Aliphatic side chain –chlorpromazine, triflupromazine.
Piperazine side chain –fluphenazine, trifluoperazine.
Piperidine side chain –thioridazine.
Butyrophenones: Haloperidol, penfluridol.
Thioxanthenes: flupenthixol.
Other heterocyclics: loxapine, pimozide.
Atypical antipsychotics: clozapine, risperidone, olanzapine, ziprasidone.
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9. CHLORPROMAZINE
• AII antipsychotics (except clozapine-like atypical) have potent dopamine D2 receptor
blocking action; antipsychotic drugs bind to D2 receptor.
• Blockade of dopaminergic projections to the temporal and prefrontal areas
constituting the 'limbic system' and in meso-cortical areas is probably responsible for
the antipsychotic action.
• As an adaptive change to blockade of D2 receptors, the firing of DA neurones and DA
turnover increases initially. But over a period of time this subsides and shows
diminished activity.
• Tolerance to DA turnover enhancing effect of antipsychotics is not prominent in the
limbic area-may account for the continued antipsychotic effect.
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10. • The antipsychotic activity of clozapine and other atypical
antipsychotics have weak D2 blocking action, but they have significant
5-HT, and α1 blocking action, and some are relatively selective for D4
receptors which is the basis for their action .
• Dopaminergic blockade in the basal ganglia appears to cause the
extrapyramidal symptoms while that in CTZ is responsible for
antiemetic action.
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11. 11

12. 1. CNS:
In Normal person : indifference to surroundings, paucity of thought, psychomotor
slowing, emotional quietening, reduction in initiative & tendency to go off to sleep.
In a psychotic patient: reduces irrational behavior, agitation & aggressiveness &
controls psychotic symptoms.
Disturbed thought & behavior are gradually normalized, anxiety is relieved.
Hyperactivity, hallucinations & delusions are suppressed.
Performance & intelligence are relatively unaffected.
Antiemetic action through CTZ.
2. ANS actions:
α adrenergic blocking activity:
CPZ = triflupromazine > thioridazine > clozapine > fluphenazine > haloperidol >
trifluoperazine > pimozide
Anticholinergic (M) acting:
thioridazine > CPZ > triflupromazine> trifluoperazine = haloperidol 12

13. 3. CVS :
postural hypotension(alpha blockade)-not prominent in psychotic
patients- reflex tachycardia accompanies
High dose Depresses heartECG changes.
antiarrhythmic action but cause arrhythmia at higher dose.
4. Local anaesthetic: potent LA but has irritant action.
5. Kidney: Decreases ADH secretion and has weak diuretic effect.
6. Endocrine:
↑ prolactin release by blocking inhibitory action of DA (may cause
galactorrhoea & gynaecomastia).
↓gonadotropin secretion, ACTH & GH.
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14. THERAPEUTIC USES
Schizophrenia
decreasing the positive symptoms: symptoms of thought disorders, restlessness,
anxiety, aggression, paranoid features, delusions, hallucinations to a lesser
degree decreasing the negative symptoms (apathy, poverty of speech, social
withdrawal).
Other selected therapeutic uses:
Mania: CPZ, haloperidol; (lithium/valproate are prefered)
Anxiety : not first choice
Antiemetic : drug/disease induced vomiting
Potentiate analgesics, anesthetics, hypnotics
intractable hiccup
Tetanus, alcoholic hallucinosis, Huntington’s disease.
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15. ADVERSE DRUG REACTIONS
Type Manifestations Mechanism
ANS, CVS Blurring of vision, dry mouth, difficulty
urinating, constipation,
Postural hypotension, palpitation,
hypotension, arrhythmia.
M- blockade
α 1 adr blockade
(Antiadrenergic)
CNS & Extra
pyramidal
disturbances
Drowsiness, lethargy, mental confusion,
seizures.(cortex decrease seizure
threshold)
Parkinson’s syndrome, acute akathisia
(motor restlessness), acute dystonia
(spasm of tongue, face, neck),
malignant neuroleptic syndrome,
Tardive dyskinesia.(basal ganglia)
Toxic -confusional state, Sedation.
D-blockade (Early
Onset)
Super sensitivity of
D receptors
(Late Onset)
M- blockade
Antihistaminergic
Endocrine
system
Hyperprolactinemia, Amenorrhea-
galactorrhea, infertility,
Impotence. (decreased GnT in
hypothalamus)
D-blockade resulting in
hyperprolactinemia
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16. • Akathisia: State of extreme motor restlessness & drive to move.
• Acute dystonia: Spasms involving head, neck, trunk & extremities, facial
grimacing , protruding tongue.
• Tardive dyskinesia (TD): Stereotyped, repetitive, involuntary movements of
the mouth, lips, tongue & choreiform movements of the limbs & body.
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18. ATYPICAL ANTIPSYCHOTICS
Clozapine:
weak D2 blockade, potent 5-HT2A antagonistic activity, H1 blocking,alpha
blockade.
It is D4 selective (less in basal ganglia)
Anticholinergicbut paradoxically induce hypersalivation.
Significant H1 blocking.
minimum extrapyramidal symptoms, rarely tardive dyskinesia, no prolactin
rise.
Low sedation.
Suppress both positive & negative symptoms
improve impaired cognitive function
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19. Limitation: agranulocytosis, sedation, unstable BP, tachycardia, urinary
incontinence, weight gain and precipitation of diabetes.
Highdose- can induce seizure
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20. NEW ANTIPSYCHOTIC DRUG
• The newest medication to reach the market for the treatment
of schizophrenia is lumateperone (also known as Caplyta and
produced by Intra-Cellular Therapies). Lumateperone was approved
by the FDA in December 2019.
• Belongs to butyrophenones but is atypical antipsychotic.
• The ability to treat schizophrenia at low EPS and low
hyperprolactinemia liability may be attributed to the
following characteristics of lumateperone: substantially greater
affinity for 5-HT2A–receptor than D2-receptor modulation, greater
than that of clozapine.
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21. REFERENCES
• Uday Kumar Padmaja. Medical Pharmacology. 4th ed. New Delhi: CBS
Publishers; 2013; pp.271-278.
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