ANTI-PSYCHOTICS LECTURE APRIL 2014

DR T. IBRAHIM

ANTI-PSYCHOTICS
(NEUROLEPTICS/MAJOR TRANQUILISERS)

Psychosis
It is a term used to describe a group of severe mental illness characterized by
hallucination, delusions, extreme abnormalities of behavior including marked over-
activity, retardation, catatonia and usually a lack of insight.

Functional psychoses: Schizophrenia and affective disorders, Schizo-affective

disorders,
mood disorders (bipolar).
Organic psychoses: secondary to pre-existing medical condition.
May be due to illicit substance use

Examples of drugs causing psychosis

Cocaine, Amphetamine, Levodopa, Methyl phenidate, Ketamine, Cannabinoids,
Steroids..

Anti-psychotic drugs
These are group of drugs used to treat psychiatric disorders characterized by
disturbed thought and behavior-primarily Schizophrenia.

Note: These drugs are notcurative and do not eliminate the chronic thought
disorder but they often decrease the intensity of hallucinations, delusions and
permit the person with Schizophrenia to function in a supportive environment.

Hallucinations
A hallucination is a perception in the absence of apparent stimulus that has qualities
of real perception. It may affect all the five senses. Auditory hallucination is very
common while visual hallucination is abit rare.

Illusion
It is a wrong or mis-interpreted perception of a sensory experience.

Delusion
A false belief that cannot be dislodged even by solid proof of contradictory evidence
or by reasoning the subject.

Bizarre delusion: very strange and completely implausible.

Non-bizarre delusion: A delusion though false but is at least possible.
Delusion of grandiosity: eg the patient is King, Queen, God.
Delusion of thought insertion: belief that another person thinks through the mind of
the person.

Schizophrenia
It comes from the Greek word meaning split and mind.
People with Schizophrenia are split off from the reality and cannot distinguish
between real and not real. It is the most common and debilitating form mental
illness.

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Three major symptoms of Schizophrenia:

1. Positive symptoms: Hallucination (auditory), delusions (Gradiosity,
persecution, Paranoid)
Catatonia (purposeless motor activity and immobility).
2. Negative symptoms: social isolation, Blunted affects, Anhedonia (Inability to
derive pleasure)
impoverished speech (alogia: absence of words),
flattening of
emotional responses.
3. Cognitive symptoms: deficit in working the memory, cognitive control of
behavior.

Epidemiology
Schizophrenia occurs in 1% of the population world-wide. It usually affects during
late adolescence or early adulthood. It has a strong genetic predisposition.

Risk factors
Environmental factors: prenatal exposure to viral infections, pre-natal poor nutrition,
per-natal hypoxia, advanced paternal age, birth rank, season of birth.

Pathogenesis
1. Dopamine Hypothesis of Schizophrenia
(no longer considered adequate to explain all aspects of Schizophrenia but enough
to understand positive and negative symptoms).
Excessive limbic dopaminergic activity plays a role in psychosis.
Post-mortem studies of Schizophrenia subjects have reported increased
dopamine levels and D2-receptor density in nucleus accumbens, caudate and
putamen.
Diminished cortical and hippocampal dopaminergic activity underlie cognitive
impairment and negative symptoms of Schizophrenia.

2. Glutamate hypothesis
Abnormal concentration of glutamate in hippocampus and pre-frontal cortex (PFC)
occurs in Schizophrenia subjects.

Note: The main neurotransmitters involved in the pathogenesis of Schizophrenia

are dopamine and glutamate.

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Anti-psychotics

First generation anti-psychotics

Acts predominantly by blocking the dopamine D2-receptors in the brain.

A. Phenothiazines: 3 groups
Group I
They are characterized by profound sedation and moderate anti-muscarinic and
Extra pyramidal side-effects, EPS.
Drugs Chlorpromazine levomeproma Promazine
zine
Dose/ro Oral/IM/PR 25-100 mg/day 100-200mg
ute Initial oral dose: 25 mg TDS (75-300 QID
mg/day)
IM: 25-500 mg q 6-8 hours
PR: 100 mg q 6-8 hours.

Remarks Limited use nowadays -------------------- ------------------

-

Group II
Fewer EPS compared to Group I and group III; moderate sedative effects.
Drugs Pericyazine Pipotiazine Mesoridazine
Dose 15-75 mg/day IM at 4 weeks interval 50-400nmg/day

Group III
Fewer sedative and anti-muscarinic effecs; more EPS compared to GP I and II.
Dru Fluphenazine Perphenazine Prochlorperazi Tri
gs decanoate ne fluoperazin
e
Dos 25 mg IM q 2 weeks Oral: 75-100 5-10 mg/day
e mg/day
IM: 12.5-25 mg
TDS

B. Butyrophenones
Benperidol
Haloperidol (3-5 mg, 2-3 times/day, max: 30 mg/day); depot preparation also
available.

C. Diphenyl butyl piperidines

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Pimozide: 2-20 mg/day ( removed due to high risk of QT elongation).

D. Piperazine
Fluphenazine

E. Thioxanthene
Thiothixene

Low potency anti-psychotics

Chlorpromazine
Prochlorperazine
Thioridazine

Moderate potency
Molindone: 15-20 mg/day

High potency Anti-psychotics

Fluphenazine
Haloperidol
Pimozide
Flupenthixol (can cause excitation and gynaecomastia)
Zuclopentixol
Sulpiride: 200-400 mg BD (maximum: 800 mg/day)

Atypical Anti-psychotics/second generation anti-psychotics

1. Aripiprazole
Dose: 15 mg OD (max: 30 mg/day); 5, 10, 15 g tabs
No weight gain
D2-partial agonist with weak 5 HT1A partial agonism.
Unlike other anti-psychotics, it lowers prolactin level and also cause nausea.
Least risk of EPS, negligible effect on QT interval and least likely to cause
hyperglycemia.

2. Clozapine
It is a di benzo-diazepine derivative.
Dose: initially 12.5-25 mg /day; maintenance of 300-600 mg by gradual titration;
25, 100mg tabs.
It has high affinity for D4 receptor; it also blocks D1, D2, 5 HT2A, -adrenoceptor and
muscarinic receptors.

Main adverse effects:

Agranulocytosis (WBC initially to be monitored every week for 2 months then
greater spacing).
Postural hypotension, collapse
Seizure 3-5%
Myocarditis and cardiomyopathy.

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Risk of weight gain and hyperglycemia:+++

Note: it is the only agent indicated to reduce risk of suicide.

3. Olanzapine
It is a thiene-benzodiazepine derivative.
It causes D1, D2, D4, 5HT2 antagonism.
Dose: 5-10 mg/day.
T1/2: 33 hours.
Weight gain/ hyperglycemia: +++
It is associated with the greatest risk of stroke in elderly patient.

4. Risperidone
Best effects seen at doses less than 6 mg/day; dose range: 0.5-10 mg/day.
Depot preparation available.

5. Paliperidone
It is the active metabolite of Risperidone.
Dose: 6 mg OD.

6. Amisulpride
Selective dopamine antagonist with high affinity for mesolimbic D 2 and D3 receptors.
Dose: 400-800 mg daily.

7. Asenapine
It is a dibenzo-oxepriopyrrole
Available for oral and sublingual use.
Dose: 10-20 mg/day; 5, 10 mg tabs.
Approved for treatment of Bipolar disorder.

8. Quetiapine
It is D1, D2, 5HT2, - receptor, H1 receptor antagonist; 5HT1A partial agonist.
Short T1/2: 6 hours
Dose: 300-450 mg/day (max:750 mg/day); start with 50 mg/day and titrate up.
Practically no EPS

Other drugs
Ziprasidone, Remoxipride, Zotepine, Sertindole (cause nasal congestion and risk of
ventricular arrhythmia), Iloperidone, Lurasidone.

Examples of anti-psychotic drugs available as Depot preparations

Protiazinepalmitate: Im every 4 weeks-50 ng/ml
Fluphenazinedecanoate: 25 mg deep IM q 2 weeks
Haloperidol decanoate: 100 mg deep IM q 4 weeks
Flupentixol: 40 mg IM q 2 weeks
Zuclopentixol: 200 mg IM q 2 weeks
Paliperidonepalmiatte, Risperidone, Ziprasidone, Aripiprazole

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Advantages of Atypical over typical anti-psychotics.

1. Able to decrease the negative symptoms of Schizophrenia; typical anti-
psychotics decrease only
the positive symptoms.
2. Absence or marked reduction in occurrence of EPS.
3. Less incidence of hyperprolactinemia (Aripiprazole actually decreases the serum
prolactin level).
4. Sexual dysfunction and skin problem are less.
5. Little effect or not effect on QT interval.
6. Atypical anti-psychotics have been found to have neuro-protective action also.
7. Better tolerance and compliance to the drug.

Disadvantages of second generation anti-psychotics

1. High risk of weight gain and hyperglycemia.
2. Risk of agranulocytosis with Clozapine.
3. Increase incidence of cardiovascular disorders.

Mechanism of action
1. All the older (first generation) and most of the newer neuroleptics block
dopamine receptors in the brain and its periphery.
Dopamine receptors: 5 types (D1, D2, D3, D4, D5)
D1andD5 receptors activate adenylyl cyclase, often exciting neurone.
D2, D3, D4 receptors: inhibit adenylyl cyclase and mediate membrane K + channel
opening leading to neuronal hyperpolarization.

Clinical efficacy of typical neuroleptics is related to their ability to block

D2receptors on mesolimbic system of the brain.
Atypical anti-psychotics have more affinity for other dopamine receptors.

Note:
Clozapine and Risperidone cause substantial blockade of -receptors which may
account for their beneficial effect on negative symptoms of Schizophrenia.

2. Serotonin-Blocking activity in brain

Most of the newer atypicalagents exert part of their action by inhibition of 5HT
receptors, particularly 5HT2A receptors.
Examples:
Clozapine: D1,D4, D2, 5HT2, muscarinic, -receptors
Olanzapine and Risperidone: 5HT2A.

Pharmacological actions
Anti-psychotics actions are due to blockade of dopamine receptors and serotonin
receptors. However, these drugs also block muscarinic, adrenergic and
histaminergic receptors, H1.

1. Anti-psychotic actions
Decreases the positive symptoms of Schizophrenia by causing D 2-
receptor blockade in mesolimbic system of brain.

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Atypical anti-psychotics such as Clozapine improve the negative

symptoms also.
Calming effects and reduction in spontaneous physical movements.

Note: Anti-psychotics take about 2-4 weeks to show optimum action.

2. Blockade of Dopamine receptors in the Nigrostriatal pathway leads to

EPS, which is characterized by Akathisia, Parkinsonism, Tardive dyskinesia,
Dystonia (sustained contraction of muscles leading to twisting and distorted
posture).
Note: Atypical anti-psychotics have less risk of causing EPS.

3. Blockade of dopamine receptors in Tubero-infundibular pathway

leads to hyperprolactinemia which in turn leads to galactorrhoea, infertility,
menstrual disturbances in females. In males, the consequence is
gynaecomastia, impotence and infertility.
Dopamine released by these neurons physiologically inhibit prolactin
secretion from the anterior pituitary.

4. Blockade of dopamine receptors in Medullary peri-ventricular pathway is

involved in eating behavior and that of Incerto-hypothalamic pathway is
involved in copulatory behavior in animal.

5. Anti-emetic effects
Most anti-psychotics (except Aripiprazole and Thioridazine) have anti emetic
action which is mediated by D2-receptor blockade in the CTZ.

6. Anti-muscarinic effects
Common with Thioridazine, Chlorpromazine, Clozapine, Olanzapine. They
lead to adverse effects such as blurring of vision, urinary retention,
constipation, dry mouth (except clozapine which despite having anti-
muscarinic action causes hypersalivation).

7. Blockade of -1 adrenergic receptors

Leads to orthostatic hypotention.

Pharmacokinetics

1. All anti-psychotic medications are highly lipophilic, highly membrane bound

or protein bound and accumulates in the brain and other tissues with rich
blood supply such as the lungs..

2. After oral administration, neuroleptics shows variable absorption which is

unaffected by food in most cases (except Ziprasidone and Paliperidone whose
absorption increase with food)
Phenothiazine are erratically absorbed after oral administration but its
absorption is good following intramuscular administration.

3. Volume of distribution varies from 7-20 L/Kg

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4. Plasma t1/2 of most anti-psychotics varies from 15-30 hours.

Examples:
Long-acting:
t1/2 Haloperidol: 18 hours
t1/2 olanzapine: 33 hours
t1/2 Aripiprazole: 3 days

Short-acting
t1/2 Quetiapine: 6 hours
t1/2 Ziprasidone: 8 hours

Some depot preparation are also available for slow release and their duration
of action varies from 2-4 weeks.
Example Fluphenazine decanoate: 2-3 weeks.

5. They are metabolized to many different substances by CYP 450 system

(particularly CYP2D6, CYP1A2, CYP3A4).

Indications

Psychiatric
1. Schizophrenia
Note: catatonic Schizophrenia is best treated managed by IV anti-psychotics.
Depot preparation can also be used for maintenance when compliance with
oral treatment is a problem.
Examples: Flupentixol decanoate.

2. Manic phase of bipolar disorder and in hypomania.

IV haloperidol for rapid control of symptoms followed by Quetiapine or
Chlorpromazine or Riseridone along with mood stabilizers.

3. Schizo-affective disorders.

4. Psychotic depression

5. For short term adjunctive management of severe anxiety associated with

psychomotor agitation, excitement, violence or impulsive behavior.

6. Senile psychosis, Alzheimer

7. Deviant social and sexual behavior: benperidol 0.25-1.5 mg/day.

Other uses
1. Anti-emetic
To treat nausea and vomiting or to prevent nausea and vomiting which
is drug induced.
Vertigo in Menieres disease.

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Labyrinthitis
Migraine

Drugs used:
Prochlorperazine: 5-20 mg/day (stemetil)
Haloperidol: 1-2 mg IM/IV
Levopromazine: 6 mg oral/sc
Benzquinamide

2. Intractable hiccups
Chlorpromazine: 10-25 mg oral q 4-6 hourly (25-50 mg IM)
Haloperidol: 1.5 mg tds

3. Pain control (in painful terminal illness)

Levopromazine 12.5mg-50 mg, Sc infusion every 24 hours.
Haloperidol + diamorphine Sc infusion.
They reduce emotional response to pain and potentiate some central effects
of narcotic analgesics.

4. Acute behavioural emergencies such as violent patients with range of

psycho-pathologies including mania and toxic delirium.
Clozapine is the only Atypical agent indicated to reduce risk of suicide.

5. As component of Neuroleptanalgesia (droperidol and Fentanyl)and

Neuroleptanaesthesia (droperidol+ Fentanyl+nitrous oxide)

6. Huntingtons chorea
Haloperidol/Risperidone (2-8 mg/day), Olanzapine
Clozapine: 50-600 mg/day
Quetiapine: 50-600 mg/day

Tetrabenazine and baclofen are also used in its management.

7. Gille de la Tourette Syndrome

Haloperidol: 0.5-1.5 mg
Olanzapine/Risperidone

8. Autism
They decrease the disruptive behaviour and irritability.
Risperidone: 0.25 mg (<25 kg); 0.5-3 mg/day (>25 kg)
Aripiprazole: 30 mg/day.

9. Pruritus
Trimeprazine is useful because of its high anti-histaminic and sedative action.

10.Anxiety disorders
Obsessive Compulsive disorder, OCD and Post Traumatic Stress Disorder,
PTSD
Drug used: olanzapine/Risperidone/Quetiapine along with SSRI

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11.Shock (off-label use)

12.Hypertension reaction complicating MAO inhibitors and TCA therapy (off label
use)

Prophylactic uses
1. Droperidol: prevention and treatment of post-operative nausea and vomiting
2. Promethazine (avomine): motion sickness.

Adverse effects
All anti-psychotics produce adverse effects that are extension of their
pharmacological action.
1. pseudo depression with older anti-psychotics due to drug induced akinesia
(respond to anti-parkinson treatment).

2. Extrapyramidal symptoms, EPS

Due to blockade of Nigrostriatal pathway
Common with first generation anti-psychotics, clozapine, olanzapine.
Least with Quetiapine.

EPS is characterized by:

i. Parkinsonism: bradykinesia, rigidity, tremors, mask facies.
Management: respond to centrally acting anti-cholinergics (Biperiden
2-12 mg, benztropine 1-6 mg) and H1-antagonist with significant
anticholinergic action such as diphenhydramine.

ii Akathisia (uncontrollable restlessness) along with dystonic reaction

(torticollis/retrocollis).
The treatmentItincorporates:
occurs after large initial dose.
1. Withdrawal of the offending drug. Replace typical anti-
Treatment: centrally
psychotics byacting anticholinergic
atypical anti-psychotics+ such
clonazepam.
as clozapine (50
mg/day), Olanzapine (5-10 mg/day), risperidone (4-10 mg/day),
Quetiapine (300-750 mg/day), Ziprasidone, Aripiprazole (10-15
mg/day to max 30mg/day), Amisulpride (800-1200 mg/day).
iii Tardive dyskinesia
Diazepam 10-20 mg/day (Gradual titration if needed) can be
used to enhance GABA- ergic activity. After discontinuation,
It is the most serous
reassess manifestation
the treatment of EPS and is usually irreversible
periodically.
2. Elimination of stimulants or
even on withdrawal of the causative agent.TCA and Anti-cholinergics drugs. with
It is most common
3. Refractory cases of choreo-athetoid or choreatic tardive
the first generation
dyskinesia can of anti-psychotics
be treated by andcatecholamine
occurs after several months
(dopamine)
to years depletors
of treatment.such as Reserpine, a small dose of 0.125 mg/day and
escalated slowly up to 6 mg/day or use Tetrabenazine initially
with 12.5 mg/day up to 200 mg/day. There is difficulty due to
dose dependent sedation and orthostatic hypotension with
these drugs.
4. Use of Lecithin is indicated as it helps in providing choline with
increasing acetylcholine in striatum.
5. Other drugs used to increase GABA ergic Transmission are:
Muscimol (5-9 mg/day), Baclofen (40-80 mg/day), Clonazepam
(1-8 mg/day) and Valproic acid (750-3000 mg/day). They
increase GABA concentration in extra- pyramidal system.
6. Vit E, if given early- it reduces voluntary movements.
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General measures
Encourage the patient, provide good nourishing diet, psychotherapy,
physiotherapy, periodic follow up and reassess therapy.
 ANTI-PSYCHOTICS LECTURE APRIL 2014
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3. Sedation and drowsiness

4. Toxic confusional stae
5. Neuroleptic Malignant Syndrome
Characterized by extreme form of rigidity, fever, unstable BP,
myoglobinemia.. it can occur as fast as the first week of therapy or after
Treatment:
months to years of treatment.
1. The most important intervention is to discontinue all antipsychotics. In
most cases, symptoms will resolve in 1-2 weeks. Neuroleptic malignant
syndrome precipitated by long-acting depot injections of antipsychotics
can last as long as a month.

2. During the course of neuroleptic malignant syndrome, use supportive

care aggressively.

3. Supportive measures are aimed at preventing further complications

and maintaining organ function.

I. Patients should receive circulatory and ventilatory support as needed.

II. Cooling blankets and antipyretics can be used to control temperature.
III. Aggressive fluid resuscitation and alkalization of urine can help prevent acute renal
failure and enhance excretion of muscle breakdown products.

4. Benzodiazepines: Diazepam 5-10mg/day. They reduce recovery time

in neuroleptic malignant syndrome and are beneficial in managing
agitated and hyperactive patients.

5. Dopaminergic agonists
Bromocriptine: Dosage very much from 2.5-5 mg TDS, the suitable
dose is 5-15mg/day to maximum 35mg/day. Every patient therapy is to
be individualized.
Other drug used is Amantadine 100-300mg/day (D1/D2 agonist).

6. Direct acting skeletal muscle relaxant

Dantrolene: 1mg/kg, IV initially, to be increased up to 10mg/kg,Iv.
After short term therapy oral medication with Dantrolene is started using
25mg/day to 100mg QID depending upon the nature and duration of the
disease. It can be given concurrently with the dopaminergic agonists.
The drug Dantrolene is hepatotoxic although rarely does it cause liver
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damage but liver function isto be monitored during therapy.

7. Treatment of complications
Hemodialysis: For preventing renal failure to occur from
rhabdomyolysis a
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6. ANS: Orthostatic hypotention,

Impotence (common with typical antipsychotics, Risperidone, Quetiapine)
Failure to ejaculate.

7. Anti-muscarinic effects
Blurring of vision, dryness of mouth (except clozapine which causes
hypersalivation- can be controlled by giving Hyoscine butyl bromide).
Urinary retention
Constipation
Increase in intra-ocular pressure.
Tachycardia with risk of arrhythmia (least with aripiprazole).

8. Effects on tubero-infundibular pathways.

First generation anti-psychotics, Amisulpride, Risperidone.
Hyper-prolactinemia (absent with aripiprazole and less with olanzapine,
clozapine, Quetiapine).
Galactorrhoea, menstrual disturbance, gynaecomastia, infertility.

9. Photoxicity, urticarial reaction.

10.Weight gain (less with Haloperidol, Aripiprazole, Loxapine).
Common with first generation anti-psychotics, Clozapine, Olazapine,
Risperidone.
11.Hyperglycemia: highest risk with Clozapine, olanzapine, Quetiapine,
Risperidone.
12.Seizure-decrease in seizure threshold.
13.Cholestatic jaundice
14.Blood dyscrasia (clozapine-agranulocytosis)
15.Cardiotoxicity (thioridazine, Pimozide, Clozapine)
16.Corneal and lens toxicity: Thioridazine-retinal deposit resembling retinitis
pigmentosa.
17.Pregnancy: dysmorphogenesis.

Drug interactions

Important drug interaction occurs when they are combined with sedatives, -
adrenergic blocking agents, anti-cholinergics and quinidine.

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Contra-indications

1. DM (especially second generation drugs such as Clozapine, olanzapine,

Quetiapine, Risperidone.
2. Patient with history of QT prolongation or severe cardiac disorders such as
myocarditis, cardiac failure.
3. Neutropenia, agranulocytosis: clozapine is contra-indicated.
4. Uncontrolled epilepsy
5. Comatoes state
6. Severe CNS depression
7. Prolactin dependent tumours
8. Severe renal and hepatic disorders.
9. Parkinsons disease
10.Angle closure glaucoma
11.BPH
12.Phaeochromocytoma
13.Myasthenia gravis with CYP 450 inhibitors.

References

1. BERTRAM,G.K., SUSAN,B. & ANTHONY, J.T.,2010. Basic and clinical pharmacology.

12th ed. US: Mc Graw Hill.
2. GOODMAN & GILMANS.,2011. The pharmacological basis of therapeutics. 12th ed.
US: Mc Graw Hill.
3. ROYAL PHARMACEUTICAL SOCIETY., 2013. BNF. London: BNF publication.
4. HARRISON., 2012. Principle of internal medicine. 18 th ed. US:Mc Graw Hill.
5. Kaplan text book of psychiatry
6. SHUKLA, J.S, 2014. Essential of therapeutics. 3rd ed

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