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� ANTIPSYCHOTIC DRUGS

Dr. Ayesha Afzal� 2022

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Learning Outcomes

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Correlate the patho-physiology of psychiatric illnesses to their management

Learning Objectives

At the end of these two lectures, MBBS 3^rd yr students will to be able to;

• Discuss the N Ts & Receptors involved in Psychosis & its pathogenesis
• Classify antipsychotics drugs. Differentiate characteristics of typical and atypical antipsychotics
• Signify the advantages of Atypical over Typical antipsychotics.

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What is PSYCHOSIS?

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It is a major mental disorder with marked “ Thought Disturbance”, “Delusions”– - -- - false believes,

and “Hallucinations”--- - false perceptions without stimuli .

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Patients loses contact with reality, hence no insight of the disorder

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VARIOUS TYPES OF PSYCHOSIS

• SCHIZOPHRENIA

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• ORGANIC PSYCHOSIS

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• SCHIZO-AFFECTIVE DISORDER

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• Depression
• Mania
• Manic depressive illness (bipolar depression)

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Pathogenesis

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Decreased dopamine release in the prefrontal cortex, and excess dopamine release in other pathways, are associated with psychotic episodes in schizophrenia and bipolar disorder.

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Dopaminergic and serotonergic pathways. Mesocortical pathway can be seen projecting to the prefrontal cortex from the VTA

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Causes of Schizophrenia

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Phases of Schizophirenia

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Genetic Analyses of Schizophrenia

Neurodevelopmental abnormalities

• Schizophrenia is considered to be a neurodevelopmental disorder.

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• Enlarge cerebral ventricles.
• Atrophy of cortical layers.
• Reduced volume of the basal ganglia.

WHAT CAUSES SCHIZOPHRENIA ?�….. THE THEORIES!�

Dopamine hypothesis- Points in favor

1. Most potent antipsychotics are potent D2 antagonists in the mesolimbic & striatal-frontal system
2. Drugs increasing levels of dopamine can produce psychosis like Ketamine & levodopa
3. There is transient rise in levels of metabolite of dopamine, in CSF, plasma & urine
4. On autopsy, dopamine levels and D2-receptor density in the nucleus accumbens, caudate, & putamen is raised

What contradicts dopamine hypothesis

1. Decreased cortical dopaminergic activity is suggested to underlie the cognitive impairment & negative symptoms of schizophrenia
2. Some antipsychotics ( atypicals) are very potent drugs but not very effective D2 receptor blockers, implying role of other receptors.
3. Atypical antipsychotic drugs share the property of weak D2-receptor antagonism & more potent 5-HT2A-receptor blockade

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Serotonergic Hypothesis

• The discovery that hallucinogens such as LSD are serotonin (5-HT) agonists led to identification of many 5-HT-receptor subtypes & the discovery that 5-HT2A-receptor and 5-HT2C stimulation was the basis for the hallucinatory effects of these agents.

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• 5-HT2A receptors modulate the release of dopamine, norepinephrine, glutamate, GABA & acetylcholine, in the cortex, limbic region, and striatum

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• 5-HT2A-receptor blockade (inverse agonists of the 5-HT2A receptor) is a key factor in the mechanism of action of the main class of second-generation antipsychotic drugs

Serotonergic Hypothesis

• 5-HT2C-receptor stimulation provides a further means of modulating cortical and limbic dopaminergic activity
• Stimulation of 5-HT2C receptors leads to inhibition of cortical and limbic dopamine release.
• Many atypical antipsychotic drugs are 5-HT2C inverse agonists.

• Recently, it has been found that hallucinogens can modulate the stability of a complex consisting of

5-HT_2A and NMDA receptors

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• Muscarinic Receptors Involvement?
• Adrenergic Receptor (a₁ & a₂) involvement

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• People with Schizophrenia appear to have a high rate of self-medication with nicotine; the therapeutic effect likely occurs through dopamine modulation by nicotinic acetylcholine receptors

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Symptoms of Schizophirenia

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(These are the result of an over activity in Mesolimbic Dopamine pathway)

There is problems with dopamine function in the mesocortical pathway.

Negative Symptoms (5As)

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PHARMACOTHERAPY OF SCHIZOPHRENIA�

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MISCELLANOUS CAUSES

METABOLIC DISORDERS affecting CNS

Electrolyte imbalance; Dehydration, Metabolic Alkalosis;

Metabolic Acidosis; Ketoacidosis; Endocrinal: Myxoedema, Vitamin deficiencies thyrotoxicosis, Hypoglycemia; Hypoxia, Hepatic or Renal failure

INFECTION OF CNS

Meningitis, Encephalitis, Cerebral Abscess

FUNCTIONAL/STRUCTURAL DISORDERS OF CNS

Epilepsies/Tumours/Pre-Senile, Dementias, Hydrocephalus, Head Injury

CEREBROVASCULAR DISORDERS OF BRAIN

Stroke/CVA

DRUG INDUCED PSYCHOSIS

• Amphetamines LD, Phencyclidin, Cannabis, Alcohol, Belladona Alkaloids, Sudden withdrawal of alcohol & CNS affecting drugs

Neuroleptic Agent

• Neuroleptic --- Greek word , lepsis (take hold of one’ nerves, or to seize ) because they suppress motor & emotional activity.

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• Neuroleptic produces a high incidence of extrapyramidal side effects (EPS) at clinically effective doses, or catalepsy in laboratory animals.

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The History - timeline

• Hydrotherapy: in the early 1800’s.
• Lobotomies (Egaz Moniz received the Nobel Prize).

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• In 1940’s Phenothiazenes were isolated & were used as pre-anesthetic medication, but quickly were adopted by psychiatrists to calm down mental pts

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• In 1955, chlorpromazine was developed as an antihistaminic agent -In-pts at Mental Hospitals dropped by 1/3.

• First-generation or typical antipsychotics, in the 1950s.

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• Most second-generation ,or atypical antipsychotics, --- clozapine, was discovered in the 1950s and introduced clinically in the 1970s.

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• Both generations of medication tend to block receptors in the brain's dopamine pathways, but atypicals tend to act on serotonin receptors as well.
• Higher concentrations of 5-HT_2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded

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Dopamine generally exerts a slow inhibitory action on CNS neurons

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DOPAMINE RECEPTOR: five subtypes:

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• D1-like receptors (D1& D5):

⇑ cAMP by Gs -coupled activation of adenylyl cyclase

• D2-like receptors (D2, D3 & D4)
• ⇓ cAMP, (by Gi–coupled inhibition of adenylyl cyclase) and
• inhibit calcium channels but open potassium channels-- ⇑K⁺ ch., ⇓Ca²⁺ch.

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Pharmacokinetics

• Readily but incompletely absorbed.
• Significant first-pass metabolism.
• Bioavailability is 25-35% with chlorpromazine and 65% with haloperidol
• Most are highly lipid soluble.
• High volume of distribution (>7 L/Kg).
• Slow elimination.
• Do not typically interfere with metabolism of other drugs.

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Pharmacokinetics

• Much longer clinical DOA than would be estimated from plasma half-lives- Prolonged occupancy of D2 receptors in the brain
• Long acting injectable formulations may cause blockade of D2 receptors for 3–6 months.
• Average time for relapse in pts who discontinue medication is 6 months.
• Clozapine is an exception - relapse after discontinuation is usually rapid & severe

It has not been demonstrated that antagonism of any dopamine receptor other than the D₂ plays a role in the action of antipsychotic drugs

D2 blockade Antipsychotic effect

The Atypical Antipsychotics

• clozapine (prototype )
• risperidone
• zotepine
• olanzapine
• quetiapine
• ziprasidone

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• aripiprazole
• sertindole
• Paliperidone
• asenapine
• lurasidone
• cariprazine

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Antipsychotic/Neuroleptics

Chlorpromazine: α₁ = 5-HT₂ = D₂ > D₁ > M > α₂

Haloperidol: D₂ > D₁ = D₄ > α₁ > 5-HT₂ >H₁>M = α₂

Clozapine: D₄ = α₁ > 5-HT₂ = M > D₂ = D₁ = α₂ ; H₁

Quetiapine: 5-HT₂ = D₂ = α₁ = α₂ ; H₁

Risperidone: 5-HT₂ >> α₁ > H₁ > D₂ > α₂ >> D₁

Sertindole: 5-HT₂ > D₂ = α₁

Receptor selectivity…

• Piperazine group has most potent D2 receptor blocking action.
• Piperidines are least potent D2 receptor blockers.
• Aliphatic group is intermediate in blocking D2 receptors.
• Butyrophenones are more potent D2 receptor blockers than phenothiazines.
• Chlorpromazine has D2 blocking activity as well as effects on alpha 1, M, serotonin & H1 receptors.
• Risperidone is used in resistant cases of Schizophrenia, it blocks D2 & serotonin receptors.

Chlorpromazine

Chlorpromazine

• Anti-dopaminergic &, Anti-serotonin ---------- Antipsychotic
• Antihistaminergic ------------ Anti- pruritic, Ant allergic & Sedative
• Anti α-adrenergic & Anti-cholinergic
• Ganglion Blocking activity
• Quinidine like effect Membrane Stabilizing….. local anaesthetic

Chlorpromazine-

1. Which receptors are blocked?
2. Positive symptoms are reduced because……….
3. Is it selective for one pathway?
4. Which other pathways are affected?
5. What is the consequence of blockade in those pathways?

CLOZAPINE

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• Prototype of Atypical antipsychotic
• D2, D4 & 5HT2A, M1 antagonist
• Has short DOA so never withdraw abruptly as relapse may occur
• More effective in negative symptoms & improves cognition
• More effective in resistant cases.
• Much less incidence of ………?
• Less incidence of Tardive Dyskinesia
• High risk of “ agranulocytosis”, Seizures, myocarditis
• Can be used in treatment of Tardive Dyskinesia, & L. dopa -Induced psychosis & bipolar disorder

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Risperidone:

• Prominent antiserotonergic(5HT_2A), antidopaminergic (D_2--like),anti adrenergic (α) and antihistaminic(H₁) and low anti muscarinic activity.
• Although atypical but can induce extrapyramidal symptoms and hyperprolactinemia but limited at low daily doses i.e.

6 mg or less with adequate antipsychotic effects

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Zipresidone Is in clinical use

• Is combined D₂/ 5HT_2A.2C,1D receptor antagonist and 5HT_1A

agonist.

• Zipresidone has an antidepressant-like effect. It inhibits 5HT and NE reuptake with moderate potency.
• Indicated for the treatment of schizopherenia and mania

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AMISULPRIDE

• Substituted benzamide
• D₂ & D₃ receptors antagonist
• t ½ = 12 hrs
• More effective than typical antipsychotic
• Improve negative symptoms
• Less EPS & Less T.D
• But Increase prolactin
• Lower weight gain

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OLANZAPINE

• Similar to clozapine chemically
• t ½ = 30 hrs
• More efficacy in negative symptoms
• Increase weight gain
• Less incidence of “ agranulocytosis”

QUETIAPINE

• Resembles clozapine but no anticholinergic
• t ½ = 3 hrs
• D1, D2 & 5HT2 antagonist
• Effective in negative symptoms
• Prolactin secretion decrease (less effective)

PHARMACOLOGICAL EFFECTS OF ANTIPSYCHOTICS

Cerebral & Limbic Cortex�

• Non – psychotic experience impaired performance, sleepiness
• In schizophrenics, emotional quietening, Psychomotor slowing, improvement in thought process, hallucinations & delusions
• Ascending reticular formation (ARF) Inhibition ---- drowsiness ------ sleep ---- but arousal easy - Quetiapine is used for sleep onset & maintenance

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Extrapyramidal System (EPS)�

• Parkinsonian syndrome, akathisia, tardive dyskinesia, Neuroleptic Malignant Syndrome & other movement disorders

Electroencephalographic Effects

• Both frequency and amplitude are altered
• Hyper synchrony - may lead to erroneous diagnostic interpretations

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Endocrine system�

• Prolactin increases with typical , risperidone , paliperidone
• FSH & LH decreases
• Peripheral conversion of androgens to estrogens increase
• False positive pregnancy test
• Amenorrheaa--- galactorrhea in females
• Gyneocomastia --- decreased libido ------in males

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Cardiovascular effects

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• Orthostatic hypotension & tachycardia……….?
• Prolongation of QT interval & abnormal configurations of ST segment & T waves---torsades de pointes -risk of sudden death ( Thioridazine , ziprasidone and quetiapine)
• Metabolic syndrome -risk of coronary artery disease, stroke & hypertension ( atypical drugs)

Central Sympathoplegic effect�

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• Pupillary constriction
• Bradycardia--- tachycardia
• Postural hypotension----- MBP decreases
• Failure of ejaculation

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• Membrane stabilizing effect--- L. anaesthesia
• ANS------ Muscarinic blockade----- Atropine like effect

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�CLINICAL INDICATIONS�

Psychiatric indications

• Schizophrenia
• Catatonic form of schizophrenia ( IV benzodiazepines )
• Schizoaffective disorders
• Manic episode of Bipolar illness
• Acute bipolar depression ( monotherapy-affective than antidepressants)
• Unipolar depression ( adjunct with antidepressants)
• Psychotic depression
• Resistant depression

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Psychiatric indications

• Anxiety disorders ( adjunct therapy in OCD & PTSD)
• Control of agitation associated with bipolar disorder & schizophrenia ( Haloperidol, ziprasidone, olanzapine, aripiprazole)
• Tourette's syndrome( Chronic Tics)
• Alzheimer disease (behavior control)

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Parkinsonism & anti-psychotics

• Medications such as levodopa in Parkinson’s disease can exacerbate psychotic symptoms.
• Likewise, antipsychotics can worsen the symptoms of Parkinson’s disease.
• New type of antipsychotic is approved for the treatment of psychosis in Parkinson’s disease.
• Pimavanserin - has no dopamine antagonist properties -not associated with EPS

Non- Psychiatric Indications

• Anti-emetic …….why? (prochlorperazine and benzquinamide)
• Anti-Pruritic ……why? ( promethazine)
• Pre-anesthetic sedation….why?
• Neuroleptanesthesia ----Droperidol
• Post surgical delirium
• Intractable Hiccough
• Huntington’s chorea

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CHOOSING THE RIGHT ANTI-PSYCHOTIC�

• Drug Choice is based mainly on differences in adverse effects & efficacy

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For treating positive symptoms:

• Typical & atypical antipsychotics are of equal efficacy in 70% pts

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For negative symptoms & cognitive impairment:

• Atypical drugs
• diminish risk of tardive dyskinesia & other forms of EPS,
• lesser increases in prolactin levels

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Criteria for selection….

• Cost and the availability -low cost of the older drugs contributes to their widespread use despite risk of EPS
• Because use of the older drugs is still widespread, knowledge agents like chlorpromazine & haloperidol is relevant
• Newer antipsychotics show superiority over haloperidol in terms of overall response
• Superior adverse-effect profile of the newer agents & absent risk of tardive dyskinesia suggest that these be the first line

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Criteria for selection….

• Atypical drugs are associated with weight gain
• Aripiprazole is the most commonly prescribed 2^nd-generation in USA
• Clozapine is limited to those patients who
• failed to respond to substantial doses of conventional drugs
• have had suicidal attempts
• Weight gain, agranulocytosis & seizures associated with clozapine prevent more widespread use

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DOSAGE, SCHEDULES & DRUG COMBINATIONS�

How to use ?

• Patients with schizophrenia have a 2-fold higher prevalence of metabolic syndrome and type 2 DM and 2-fold greater CV-related mortality rates than the general population
• . For this reason, consensus guidelines recommend baseline determination of
• serum glucose, lipids, weight, blood pressure, and personal and family histories of metabolic and CV disease.
• Short-Term Treatment
• Long-Term Treatment

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Dosage

• Therapeutic margins are broad
• Pts who become refractory to 2-3 antipsychotic agents in substantial doses are candidates for treatment with …………..?

Parenteral Preparations

• Haloperidol & Fluphenazine depot forms are available for rapid initiation of treatment & maintenance treatment in noncompliant pts.
• Doses should be only a fraction of oral dose
• Newer long-acting injectable (LAI) second-generation antipsychotics are now available

Dosage Schedules

• Initially given in divided daily doses, titrating to the effective dosage.
• Started with lower dose& gradually increased to effective dose
• Eventually Once-daily doses, usually given at night

Drug Combinations

• TCAs & SSRIs
• ECT is a useful adjunct
• Lithium or Valproic acid
• BZs for pts with anxiety or insomnia

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ADVERSE EFFECTS�

The acute adverse effects of antipsychotics are due to

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Blockade of D₂ receptors

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Presynaptic Compensatory Effects

Firing rate and activity of nigro-striatal and meso-limbic DA neurons.

• DA synthesis, DA metabolism, DA release.( causing acute adverse effects )

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Postsynaptic Depolarization Blockade

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Inactivation of nigro-striatal and meso-limbic DA neurons.

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Receptor Supersensitivity (producing late Adverse effects)

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A) Behavioral Effects

B) Neurological Effects ( early & late )

• Acute dystonic reactions
• Akathisia ( uncontrolled restlessness)
• Parkinson-like symptoms ( Levodopa is never used)
• Neuroleptic Malignant syndrome
• Seizures
• Peri-oral Tremors
• Tardive Dyskinesia - Late

C. Autonomic effects

D . Metabolic & Endocrine effects

E . Cardiac effects (prolongation of QT interval)

F . Ocular complications ( retinal pigmentation)

G . Dysmorphogenesis in Pregnancy

H . Toxic or Allergic Reactions

• Skin rash
• Cholestatic jaundice

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A: Behavior effects

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• Unpleasant to take- non compliance
• Given in low doses during the day & higher at night
• “Pseudo depression” - may be due to drug-induced akinesia
• Toxic confusional state at high doses

B: Neurological effects ( early)

Acute dystonic reactions

• Involves spasm of muscles of tongue, face, neck, back; ---may mimic hysteria-
• spastic retrocollis or torticollis
• Managed with diphenhydramine

Parkinsonism

• Can be treated with conventional ant parkinsonism drugs of the antimuscarinic type
• Levodopa should never be used in these patients ………….?
• Parkinsonism may be self-limiting-
• an attempt to withdraw antiparkinsonism drugs be made every 3–4 months

Akathisia

• Uncontrollable restlessness
• Responds to anti-histamines with anticholinergic properties ( diphenhydramine)

B: Neurological effects ( late)

Peri-oral tremors ( Rabbit’s syndrome)

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Tardive Dyskinesia

• (20-40% pts on chronic therapy)
• most important untoward effect- Occurs after years of therapy
• Irreversible , must be avoided

Presents as:

• Involuntary repetitive body movements- grimacing sticking out tongue, lip smacking
• Choreoathetoid movements- rapid jerky movements or slow writhing movements

Tardive Dyskinesia

Cause:

• Increased nigrostriatal dopaminergic activity
• result of post synaptic receptor super sensitivity in caudate putamen
• upregulation from chronically high levels of D2 blockade
• May be reduced temporarily by increasing the drug dose suggesting the cause to be dopamine receptor sensitization
• Relative cholinergic deficiency

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Tardive Dyskinesia

Treatment:

• Discontinue or reduce the dose of drug
• Eliminate all drugs with central anticholinergic effect
• Switch to atypical Clozapine or Quetiapine
• Diazepam 30-40mg/d may add to the improvement by enhancing GABAergic activity

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B: Neurological Effects

Seizures

• Seen with chlorpromazine
• lower incidence with high-potency older drugs
• Occur in 2–5% of pts on clozapine.

Neuroleptic Malignant syndrome; early in treatment

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• A severe form of EPS
• Life-threatening disorder occurs in pts who are extremely sensitive to EPS effects
• Results from an excessively rapid blockade of postsynaptic dopamine receptors

Signs /Symptoms

• Marked muscle rigidity-CKMB elevation
• Signs of autonomic instability, altered blood pressure & pulse rate
• Fever with stress leukocytosis- imitate infection
• Changes in mental state

Treatment:

• Supportive- cooling
• Aggressive therapy Anti-parkinsonism drugs like Bromocriptine
• Diazepam & Dantrolene
• Switching to atypical drugs

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C: Cardiac toxicity

• Thioridazine > 300 mg associated with abnormalities of T waves .
• Higher doses are associated with ventricular arrhythmias, eg, torsades de pointes, conduction blocks

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• Ziprasidone carries the greatest risk of QT prolongation -should not be combined with other drugs that prolong the QT interval -thioridazine, pimozide, & group 1A or 3 antiarrhythmic drugs.

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• Clozapine is associated with myocarditis and must be discontinued if it appears.

D: Autonomic effects

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Thioridazine has the strongest & haloperidol has the weakest autonomic effects. Newer drugs have intermediate autonomic effects

• Some have effects at muscarinic acetylcholine receptors:
• dry mouth, blurred vision, urinary retention constipation

• Some have effects at α-adrenergic receptors:
• orthostatic hypotension & impaired ejaculation

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• Some have effects at H1-histaminergic receptors:
• Sedation

E: Allergic reactions

• Cholestatic jaundice, skin eruptions
• Clozapine causes agranulocytosis in 1–2% of pts
• fatal effect can develop rapidly
• reversible upon discontinuance of the drug

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Because of the risk of agranulocytosis, pts receiving clozapine must have weekly blood counts for first 6 months & every 3 weeks thereafter

F:Retinal complications

• Chlorpromazine may cause deposits in the anterior portions of the eye
• Thioridazine is the only antipsychotic drug that causes retinal deposits, resemble retinitis pigmentosa.
• “browning” of vision

G:Endocrine effects

• Increase in Prolactin levels – common with older as well as risperidone ( switch to aripiprazole)
• Galactorrhea , Amenorrhea in female
• Loss of libido & Gynecomastia in males

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H: Weight gain & Metabolic effects

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• Clozapine & olanzapine have highest incidence of Hyperlipidemia & Hyperglycemia
• Monitoring weight at each visit and measurement of fasting blood sugar & lipids at 3- to 6-month interval
• Ziprasidone is the atypical drug causing the least weight gain.

Drug Interactions

• Additive effects with sedatives , anticholinergics, antihistaminics effects

A 17 year old male diagnosed with schizophrenia was treated with Fluphenazine. Three days later, he developed a high body temperature and lead-pipe rigidity.

Which of the following would be appropriate treatment for this patient?

1. Continue with Fluphenazine and administer an anticholinergic
2. Continue with Fluphenazine and administer a benzodiazepine
3. Discontinue Fluphenazine and administer haloperidol
4. Discontinue Fluphenazine and administer dantrolene

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Overdose

• Poisoning rarely fatal- have high TI
• Exception is Thioridazine-----Induction of ventricular tachycardia
• Drowsiness proceeds to coma with intervening agitation
• Convulsions
• Pupils meiotic
• Deep tendon reflexes increased
• Hypotension & hypothermia

Treatment

• “ABCD” for poisoning - Gastric lavage
• Cardiac arrhythmias management

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Merits of newer anti-psychotics

• Lesser EPS incidence
• More effective in treating “ negative symptoms”
• Equal efficacy in treating “ positive symptoms”
• Lesser risk of “Tradive Dyskinesia”
• Lesser effects on “ Prolactin Secretion”
• Patients not responding to “Typical Antipsychotics” respond well to these

Demerits of newer drugs�

• Weight gain
• Lipid profile deranged
• Hyperglycemia- insulin resistance
• Agranulocytosis
• Cholestatic Jaundice
• Seizures
• Costly

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Differences B/W Typical & Atypical Antipsychotics

MCQs

  A 33 year old female was brought to hospital by her husband for acute change in mental status.  He reports that she has been taking the same medication to treat symptoms of anxiety and paranoia for the past year.  On examination the woman is diaphoretic, with some rigidity of her extremities.  Her blood pressure is 198/109, Temperature 101 0. Blood analyses show grossly elevated creatine kinase. 

Which of the following medications could have caused her serious condition?

1. Clozapine
2. Dantrolene
3. Asenapine
4. Quetiapine
5. Fluphenazine

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A 35-year-old man with abnormal behaviour has been diagnosed with schizophrenia.

Which of the following symptom in schizophrenia, is most effectively treated with Clozapine than haloperidol?

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1. Hallucinations
2. Bizarre delusions
3. Delusions
4. Social withdrawal

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• A 17 year old male diagnosed with schizophrenia was treated with Fluphenazine. Three days later, he developed a high body temperature and lead-pipe rigidity.
• Which of the following would be appropriate treatment for this patient?
• Discontinue Fluphenazine and administer haloperidol
• Continue with Fluphenazine and administer an anticholinergic
• Continue with Fluphenazine and administer a benzodiazepine
• Discontinue Fluphenazine and administer dantrolene

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