Explain about anti psychotic drugs

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antipsychotic drugs clinical pharmacology

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Antipsychotic Drugs

Antipsychotics are a class of medications used primarily to manage psychotic disorders, especially schizophrenia, but they have a wide range of other psychiatric applications. They do not cure the underlying condition but reduce the intensity of symptoms like hallucinations and delusions.

1. Overview and Indications

Primary use: Schizophrenia (positive symptoms: hallucinations, delusions, disorganized thought; and to some extent negative symptoms: avolition, social withdrawal, blunted affect)

Other uses:

Bipolar disorder (manic, mixed, and depressive episodes)
Treatment-refractory depression (as augmentation)
Tourette disorder (haloperidol, risperidone, pimozide)
Autism-related irritability/disruptive behavior (risperidone, aripiprazole)
Schizoaffective disorder (paliperidone)
Antiemetic use (prochlorperazine, chlorpromazine)
Intractable hiccups (chlorpromazine, historically)
Acute agitation management
Lippincott Illustrated Reviews: Pharmacology, p. 610

2. Pathophysiology Basis (Why They Work)

Four key dopamine tracts relevant to antipsychotic pharmacology:

Tract	Role	Effect of Antipsychotics
Mesolimbic	Positive symptoms (hallucinations, delusions)	Blockade reduces positive symptoms
Mesocortical	Negative symptoms, cognition	Blockade may worsen negative symptoms
Nigrostriatal	Motor control	Blockade causes EPS (extrapyramidal side effects)
Tuberoinfundibular	Prolactin regulation	Blockade raises prolactin (hyperprolactinemia)

The dopamine hypothesis proposes that psychosis results from hyperdopaminergic activity in the mesolimbic tract. All currently effective antipsychotics block dopamine D2 receptors to some degree.

Lippincott Illustrated Reviews: Pharmacology, p. 611

3. Classification

First-Generation Antipsychotics (FGAs) - "Typical" or "Conventional"

Also called neuroleptics or major tranquilizers. Their primary mechanism is D2 receptor blockade. Further divided by receptor affinity/potency:

Low Potency (higher anticholinergic, antihistamine, alpha-blocking effects; less EPS):

Chlorpromazine (prototype)
Thioridazine

High Potency (tighter D2 binding; more EPS risk):

Haloperidol (Haldol) - most widely used FGA
Fluphenazine
Trifluoperazine
Perphenazine
Thiothixene
Loxapine
Pimozide
Prochlorperazine
Molindone

"No one drug is clinically more effective than another" - the distinction of potency refers to D2 affinity, not clinical superiority.

Second-Generation Antipsychotics (SGAs) - "Atypical"

These block both 5-HT2A (serotonin) and D2 (dopamine) receptors. This dual blockade accounts for lower EPS and some benefit on negative symptoms compared to FGAs.

Drug	Brand	Notable Feature
Clozapine	Clozaril	Reserved for refractory cases; risk of agranulocytosis
Risperidone	Risperdal	Also used in autism, Tourette
Olanzapine	Zyprexa	High metabolic side effect risk
Quetiapine	Seroquel	Also for bipolar depression
Aripiprazole	Abilify	Partial D2 agonist; low metabolic risk
Ziprasidone	Geodon	Least weight gain; absorption increased with food
Paliperidone	Invega	Active metabolite of risperidone; approved for schizoaffective disorder
Lurasidone	Latuda	Bipolar depression; absorption increased with food
Asenapine	Saphris	Sublingual and transdermal formulations
Brexpiprazole	Rexulti	Adjunct for depression
Cariprazine	Vraylar	D3/D2 partial agonist; bipolar depression
Lumateperone	Caplyta	Newer agent; schizophrenia and bipolar depression
Iloperidone	Fanapt
Pimavanserin	Nuplazid	5-HT2A inverse agonist; Parkinson's psychosis only

Lippincott Illustrated Reviews: Pharmacology, pp. 610-611

4. Mechanism of Action

Drug Class	Receptor Actions
FGAs	D2 blocker + variable H1, muscarinic M1, alpha-1 blockade
SGAs (most)	D2 + 5-HT2A blocker
Aripiprazole, brexpiprazole, cariprazine	Partial D2/D3 agonists + 5-HT1A partial agonists
Pimavanserin	Selective 5-HT2A inverse agonist (no D2 activity)

Why 5-HT2A blockade matters: Serotonin inhibits dopamine release in the nigrostriatal and mesocortical pathways. Blocking 5-HT2A disinhibits dopamine release in these areas, reducing EPS risk and potentially improving negative/cognitive symptoms.

5. Adverse Effects

Extrapyramidal Symptoms (EPS) - mainly FGAs

Type	Onset	Features	Treatment
Acute dystonia	Hours-days	Sustained muscle contractions, torticollis, oculogyric crisis	Anticholinergics (benztropine, diphenhydramine)
Akathisia	Days-weeks	Restlessness, inability to sit still	Beta-blockers, benzodiazepines, propranolol
Parkinsonism	Weeks	Tremor, rigidity, bradykinesia, masked face	Amantadine, anticholinergics
Tardive dyskinesia (TD)	Months-years	Repetitive, involuntary oral-facial movements	D2 blockers cause upregulation of D2 receptors; treat by stopping drug, switching; VMAT2 inhibitors (valbenazine, deutetrabenazine)

Metabolic Effects (mainly SGAs)

Weight gain (olanzapine and clozapine are worst)
Hyperglycemia and new-onset type 2 diabetes
Dyslipidemia, hypercholesterolemia
Metabolic syndrome

A 2025 meta-analysis in JAMA Psychiatry (PMID 40864439) confirmed that antipsychotics are significantly associated with dysregulated glucose homeostasis, with second-generation agents carrying the highest risk.

Hyperprolactinemia (tuberoinfundibular blockade)

Galactorrhea, amenorrhea, gynecomastia, sexual dysfunction
Worst with risperidone, haloperidol
Less/no risk: aripiprazole (partial agonist), quetiapine, clozapine

Anticholinergic Effects (especially low-potency FGAs, clozapine)

Dry mouth, constipation, urinary retention, blurred vision, cognitive impairment

Cardiovascular Effects

QTc prolongation (thioridazine, ziprasidone, haloperidol IV) - risk of torsades de pointes
Orthostatic hypotension (alpha-1 blockade - especially chlorpromazine, clozapine)
Myocarditis (clozapine - rare but serious)

Sedation

Prominent with low-potency FGAs and clozapine (strong H1 antihistamine blockade)

Clozapine-Specific Risks

Agranulocytosis (1-2%) - requires mandatory weekly/biweekly CBC monitoring (REMS program)
Seizures
Severe weight gain and metabolic effects
Sialorrhea (paradoxical hypersalivation)
Myocarditis (early treatment period)

6. Pharmacokinetics

Variable oral absorption; food increases absorption of ziprasidone, lurasidone, paliperidone
Highly lipophilic; large volume of distribution; cross blood-brain barrier readily
Metabolized by CYP450 system, primarily CYP2D6, CYP1A2, CYP3A4
Smoking induces CYP1A2 - reduces levels of clozapine and olanzapine significantly
Active metabolites: paliperidone (from risperidone), amoxapine (from loxapine)
Lippincott Illustrated Reviews: Pharmacology, p. 619

7. Long-Acting Injectable (LAI) Formulations

Designed to improve medication adherence. Therapeutic duration varies from 2-4 weeks up to 6 months:

Drug	LAI Name	Interval
Haloperidol decanoate	Haldol Decanoate	Every 4 weeks
Fluphenazine decanoate	Generic	Every 2-4 weeks
Risperidone microspheres	Risperdal Consta	Every 2 weeks
Paliperidone palmitate	Invega Sustenna	Every 4 weeks
Paliperidone palmitate 6-mo	Invega Hafyera	Every 6 months
Aripiprazole monohydrate	Abilify Maintena	Every 4 weeks
Olanzapine pamoate	Zyprexa Relprevv	Every 2-4 weeks

Most are IM; risperidone suspension and fluphenazine decanoate may also be given subcutaneously.

Lippincott Illustrated Reviews: Pharmacology, p. 619

8. Neuroleptic Malignant Syndrome (NMS)

A rare but potentially fatal reaction to antipsychotics, characterized by:

"FALTER" mnemonic: Fever (hyperthermia), Autonomic instability, Leukocytosis, Tremor/rigidity (lead-pipe), Elevated CPK, Reduced consciousness
Management: Stop the drug immediately, supportive care, dantrolene, bromocriptine

9. Drug Selection Summary

Situation	Preferred Agent
First-line schizophrenia	SGA (e.g., risperidone, olanzapine, aripiprazole)
Refractory schizophrenia	Clozapine
Parkinson's psychosis	Pimavanserin (no D2 blockade)
Bipolar depression	Lurasidone, cariprazine, quetiapine
Suicide risk in schizophrenia	Clozapine
Tourette disorder	Haloperidol, risperidone, pimozide
Minimizing EPS	SGAs preferred over FGAs
Minimizing weight gain	Ziprasidone, aripiprazole, lurasidone
Minimizing QTc	Aripiprazole, lurasidone

10. Recent Evidence Updates

A 2025 network meta-analysis in JAMA Psychiatry (PMID 39412783) found significant differences among antipsychotics in their effects on cognitive function, with clozapine and some SGAs showing more favorable profiles.
A 2025 meta-analysis (PMID 40864439) confirmed robust associations between antipsychotic use and dysregulated glucose homeostasis, reinforcing the need for metabolic monitoring for all patients on these drugs.

Sources: Lippincott Illustrated Reviews: Pharmacology (18th ed.); Katzung's Basic and Clinical Pharmacology, 16th Ed.; Kaplan & Sadock's Comprehensive Textbook of Psychiatry; The Maudsley Prescribing Guidelines in Psychiatry, 15th Ed.

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