Antipsychotics

Antipsychotics (neuroleptics) are the cornerstone of treatment for schizophrenia, acute psychosis, mania, and several off-label uses. They are split into typical (first-generation, FGA) and atypical (second-generation, SGA) agents, and almost every exam-relevant fact flows from one core mechanism — dopamine D2 receptor blockade — and its consequences across the four dopaminergic pathways.

Definition & classification

Antipsychotics relieve the positive symptoms of psychosis (delusions, hallucinations, thought disorder) primarily by antagonising dopamine D2 receptors in the mesolimbic pathway. Atypicals additionally act on serotonin 5-HT2A receptors, which improves negative symptoms (apathy, flat affect, social withdrawal) and dramatically lowers the rate of extrapyramidal side effects (EPS).

Class	Prototype drugs	Receptor profile	EPS risk	Key signature
Typical – high potency	Haloperidol, fluphenazine, trifluoperazine, pimozide	Strong D2 block, weak anticholinergic	High	Maximum EPS, least sedation/hypotension
Typical – low potency	Chlorpromazine, thioridazine	Weaker D2, strong M/H1/α1 block	Moderate	Sedation, hypotension, anticholinergic
Atypical	Clozapine, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone	D2 + 5-HT2A block	Low	Metabolic syndrome, weight gain

High-yield: "Potency" in antipsychotics refers to the dose needed, not efficacy — all antipsychotics have roughly equal efficacy against positive symptoms (except clozapine, which is superior in refractory cases). High-potency drugs work at low doses but cause more EPS; low-potency drugs need large doses and cause more autonomic/sedative effects.

A useful sub-grouping by chemistry: Phenothiazines (chlorpromazine — aliphatic; thioridazine — piperidine; fluphenazine, trifluoperazine — piperazine), Butyrophenones (haloperidol), Thioxanthenes (flupenthixol), and the atypicals (mostly "-apine"/"-idone"/"-piprazole" suffixes).

Mechanism & the four dopamine pathways

D2 blockade is therapeutic in one pathway but causes adverse effects in three others — this single concept generates the bulk of MCQs.

Pathway	Normal function	Effect of D2 blockade
Mesolimbic	Mediates positive symptoms	Therapeutic — reduces hallucinations/delusions
Mesocortical	Cognition, negative symptoms	Worsens negative symptoms (already hypodopaminergic)
Nigrostriatal	Motor control	EPS (dystonia, parkinsonism, akathisia, tardive dyskinesia)
Tuberoinfundibular	Dopamine inhibits prolactin	Hyperprolactinaemia → galactorrhoea, amenorrhoea, gynaecomastia

Threshold concept: Antipsychotic effect typically appears at ~65–70% striatal D2 occupancy, EPS at >80%, and hyperprolactinaemia at >72%. This narrow window explains why high-potency typicals cause EPS readily.

Atypicality explained: A high 5-HT2A:D2 affinity ratio + rapid D2 dissociation ("loose binding", e.g. quetiapine, clozapine) → less nigrostriatal blockade → fewer EPS. Aripiprazole is unique: a D2 partial agonist ("dopamine system stabiliser") — it acts as a functional antagonist where dopamine is high (mesolimbic) and an agonist where it is low.

High-yield: 5-HT2A antagonism is the defining feature of atypicals and the reason they cause less EPS and treat negative symptoms better. Aripiprazole = D2 partial agonist.

Clinical uses

• Schizophrenia — drug of first choice is an atypical (risperidone/olanzapine) for new diagnoses.
• Acute psychosis / agitation / delirium — IM haloperidol (often with lorazepam).
• Mania — adjunct/monotherapy (olanzapine, risperidone, quetiapine).
• Tourette syndrome / tics — haloperidol, pimozide, aripiprazole.
• Huntington's chorea — D2 block suppresses chorea (tetrabenazine preferred).
• Antiemesis — prochlorperazine, chlorpromazine (D2 block in CTZ).
• Intractable hiccups — chlorpromazine.
• Treatment-resistant schizophrenia & reduction of suicidality — clozapine (the only agent with proven superiority here).

Adverse effects

Extrapyramidal side effects (EPS) — chronological pattern

A classic stepwise time-course is heavily tested:

Hours–days → Acute dystonia (oculogyric crisis, torticollis, laryngospasm) — most common in young males. ↓ Days–weeks → Akathisia (motor restlessness, inability to sit still — commonly mistaken for worsening psychosis). ↓ Weeks–months → Parkinsonism (bradykinesia, rigidity, tremor). ↓ Months–years → Tardive dyskinesia (orofacial chorea, lip-smacking, tongue protrusion).

EPS type	Onset	Treatment
Acute dystonia	Hours–days	IV/IM anticholinergic (benztropine, promethazine) or diphenhydramine
Akathisia	Days–weeks	Propranolol (β-blocker), benzodiazepine; reduce dose
Parkinsonism	Weeks–months	Anticholinergic (trihexyphenidyl, benztropine); reduce dose. Never use levodopa (worsens psychosis)
Tardive dyskinesia	Months–years	Stop/switch to atypical (clozapine); VMAT2 inhibitors — valbenazine, deutetrabenazine, tetrabenazine

High-yield: Tardive dyskinesia is often irreversible. Anticholinergics worsen TD (unlike acute dystonia/parkinsonism where they help). Highest risk with long-term high-potency typicals, elderly, and women. First-line treatment is now a VMAT2 inhibitor.

Mnemonic for EPS order — "ADAPT": Acute dystonia → Akathisia → Parkinsonism → Tardive dyskinesia (with the first two being early, the last two late).

Neuroleptic malignant syndrome (NMS)

A life-threatening idiosyncratic reaction from excessive D2 blockade, classically with high-potency typicals (haloperidol) but possible with any agent, including atypicals and antiemetics (metoclopramide).

Tetrad (mnemonic "FEVER"): Fever (hyperthermia, >40°C), Encephalopathy (altered mental status), Vitals unstable (autonomic dysregulation — labile BP, tachycardia), Elevated enzymes (CK markedly raised, leukocytosis), Rigidity ("lead-pipe").

• Onset: typically within the first 1–2 weeks of starting/increasing the drug; develops over 1–3 days.
• Investigations: ↑↑ CK (often >1000, can reach 100,000), leukocytosis, ↓ serum iron, myoglobinuria → risk of acute kidney injury from rhabdomyolysis.

Management flow: Stop the antipsychotic → aggressive cooling + IV fluids → dantrolene (muscle relaxant) ± bromocriptine/amantadine (dopamine agonists) → benzodiazepines for agitation → ICU supportive care.

Feature	NMS	Serotonin syndrome	Malignant hyperthermia
Trigger	D2 blocker	Serotonergic drugs	Volatile anaesthetic/succinylcholine
Onset	Days (1–3)	Hours (<24 h)	Minutes (intra-op)
Neuromuscular	Lead-pipe rigidity, bradyreflexia	Hyperreflexia, clonus, myoclonus	Rigidity
Pupils	Normal	Mydriasis	—
Antidote	Dantrolene + bromocriptine	Cyproheptadine	Dantrolene

High-yield: Lead-pipe rigidity + hyporeflexia = NMS; clonus/hyperreflexia + mydriasis = serotonin syndrome. Both can be treated with dantrolene, but the specific antidotes differ (bromocriptine vs cyproheptadine).

Metabolic and endocrine effects

Atypicals (especially clozapine and olanzapine) cause the worst metabolic syndrome — weight gain, dyslipidaemia, hyperglycaemia/new-onset diabetes. Monitor weight, fasting glucose, and lipids regularly.

High-yield (memory aid): Worst metabolic risk → "Clozapine, Olanzapine" (think "Clo-Ol" for the highest weight gain). Lowest metabolic risk → aripiprazole, ziprasidone, lurasidone. Ziprasidone is weight-neutral but prolongs QT the most.

Hyperprolactinaemia is greatest with risperidone (among atypicals) and high-potency typicals → amenorrhoea, galactorrhoea, gynaecomastia, sexual dysfunction, and long-term osteoporosis. Aripiprazole can lower prolactin.

Receptor-block-related adverse effects

• Anticholinergic (muscarinic): dry mouth, blurred vision, constipation, urinary retention — chlorpromazine, thioridazine, clozapine, olanzapine.
• α1-adrenergic: orthostatic hypotension — chlorpromazine, clozapine, risperidone.
• H1 (histamine): sedation, weight gain — chlorpromazine, clozapine, olanzapine, quetiapine.

Drug-specific toxicities (very high-yield)

Drug	Signature toxicity
Clozapine	Agranulocytosis (mandatory monitoring), seizures (dose-dependent), myocarditis, severe constipation/ileus, excess salivation (hypersalivation), weight gain
Thioridazine	Retinitis pigmentosa (retinal deposits), QT prolongation, inhibits ejaculation
Chlorpromazine	Corneal/lens deposits, photosensitivity, blue-grey skin, cholestatic jaundice
Ziprasidone	Maximum QT prolongation
Pimozide / haloperidol	QT prolongation, torsades
Quetiapine	Most sedating, cataracts (monitor)

Clozapine — the special case

Clozapine is reserved for treatment-resistant schizophrenia (failure of ≥2 adequate antipsychotic trials) and to reduce suicidality. It has the lowest EPS and essentially no tardive dyskinesia / hyperprolactinaemia, but its use is restricted by serious toxicity.

High-yield: Clozapine causes agranulocytosis (~1%) — it requires mandatory haematological monitoring (absolute neutrophil count, ANC): weekly for the first 6 months, then fortnightly to 12 months, then monthly. Stop clozapine if ANC < 1500/µL (severe neutropenia < 500/µL). Agranulocytosis is not dose-related, whereas clozapine-induced seizures are dose-related.

Other clozapine pearls: it does not cause significant EPS (so it is the antipsychotic of choice in Parkinson's disease psychosis and to treat established tardive dyskinesia), but it carries risks of myocarditis/cardiomyopathy (monitor early), fatal bowel ileus, and hypersalivation (paradoxical, despite anticholinergic action). Re-challenge is contraindicated after agranulocytosis.

Diagnosis & monitoring (investigation of choice)

Antipsychotic therapy is largely a clinical diagnosis-driven intervention; "investigation of choice" questions revolve around monitoring:

• Before starting: weight/BMI, waist circumference, fasting glucose & lipids, ECG (baseline QTc), prolactin if symptomatic, FBC (mandatory baseline ANC for clozapine).
• NMS: serum CK (markedly elevated) is the key lab clue.
• Clozapine: serial ANC is the answer for "monitoring of choice."
• Thioridazine: baseline + periodic ophthalmic examination (retinopathy).
• QT-prolonging agents (ziprasidone, pimozide, haloperidol): ECG (QTc) monitoring.

Management principles & drug of choice

1. Newly diagnosed schizophrenia → start an atypical (risperidone or olanzapine).
2. Acute agitation/psychosis → IM haloperidol ± lorazepam (or IM olanzapine — but do not combine IM olanzapine with parenteral benzodiazepine — risk of cardiorespiratory depression).
3. Treatment-resistant (≥2 failed trials) → clozapine.
4. Poor adherence → long-acting depot injection (haloperidol decanoate, fluphenazine decanoate, paliperidone palmitate, risperidone microspheres).
5. Acute dystonia → IV anticholinergic/diphenhydramine.
6. Akathisia → propranolol.
7. Tardive dyskinesia → switch to clozapine + VMAT2 inhibitor.
8. NMS → stop drug + dantrolene + bromocriptine + supportive care.

High-yield: Haloperidol is the drug of choice for acute agitation/delirium and for the most rapid IM control; clozapine is the drug of choice for refractory schizophrenia; atypicals are first-line overall.

Complications & long-term concerns

• Cardiovascular: QT prolongation → torsades de pointes (thioridazine, ziprasidone, pimozide, haloperidol); orthostatic hypotension.
• Metabolic syndrome → cardiovascular morbidity (clozapine, olanzapine).
• Sudden cardiac death — modestly increased risk; increased mortality in elderly with dementia-related psychosis (black-box warning — antipsychotics should be avoided/minimised here).
• Seizure threshold lowering (clozapine, chlorpromazine most).
• Tardive dyskinesia — irreversible movement disorder.
• Venous thromboembolism, lowered seizure threshold, and anticholinergic delirium in the elderly.

Key differentials & comparisons

• NMS vs serotonin syndrome vs malignant hyperthermia — distinguished by trigger, time-course, and neuromuscular findings (rigidity + hyporeflexia vs clonus + hyperreflexia) — see table above.
• Akathisia vs psychotic agitation — akathisia is objective motor restlessness that worsens with dose increase; mistaking it for relapse and increasing the dose is a classic error.
• Tardive dyskinesia vs acute dystonia — TD is late, choreiform, worsened by anticholinergics; acute dystonia is early, sustained, relieved by anticholinergics.
• Parkinsonism (drug-induced) vs idiopathic PD — drug-induced is typically symmetrical and reversible on stopping the offending agent.

Recently asked / exam angle

• "Loose D2 binding / rapid dissociation" explaining atypicality — frequently asked (quetiapine, clozapine).
• Aripiprazole = D2 partial agonist — repeatedly tested single-best-answer.
• Clozapine + agranulocytosis + ANC-based monitoring and clozapine for refractory/suicidal patients — perennial favourite.
• NMS tetrad, lead-pipe rigidity, raised CK, dantrolene + bromocriptine — image/clinical-vignette MCQs.
• VMAT2 inhibitors (valbenazine/deutetrabenazine) for tardive dyskinesia — newer high-yield addition.
• Thioridazine → retinitis pigmentosa; chlorpromazine → corneal/lens deposits + photosensitivity — classic drug-toxicity matching.
• Ziprasidone → maximum QT prolongation; olanzapine/clozapine → maximum weight gain — comparison MCQs.
• Propranolol for akathisia — a recurring one-liner.
• Risperidone → highest prolactin among atypicals.
• Hyperprolactinaemia mechanism (tuberoinfundibular D2 block).

Rapid revision

1. D2 blockade in mesolimbic pathway treats positive symptoms; blockade elsewhere causes EPS, hyperprolactinaemia, worsened negatives.
2. Atypicals = D2 + 5-HT2A antagonism → less EPS, better negative-symptom control.
3. Aripiprazole = D2 partial agonist; can lower prolactin.
4. EPS order: dystonia → akathisia → parkinsonism → tardive dyskinesia.
5. Acute dystonia → anticholinergic; akathisia → propranolol; TD → VMAT2 inhibitor + switch to clozapine.
6. Tardive dyskinesia is irreversible and worsened by anticholinergics.
7. NMS: fever + lead-pipe rigidity + autonomic instability + altered sensorium + ↑↑CK → stop drug, dantrolene + bromocriptine.
8. Clozapine = best for refractory schizophrenia + reduces suicidality; causes agranulocytosis → mandatory ANC monitoring; seizures are dose-related.
9. Olanzapine & clozapine = worst weight gain/metabolic syndrome; ziprasidone weight-neutral but maximal QT.
10. Risperidone = highest prolactin among atypicals.
11. Thioridazine → retinitis pigmentosa & QT; chlorpromazine → corneal deposits, photosensitivity, blue-grey skin, cholestatic jaundice.
12. Haloperidol = drug of choice for acute agitation/delirium; high EPS, low sedation.