Which atypical antipsychotic has the LOWEST risk of causing extrapyramidal side effects (EPS) and tardive dyskinesia, and why?
- A Clozapine — because of high D4/5-HT2A receptor affinity and loose, rapidly dissociating D2 binding ✓
- B Risperidone — because it is a pure D2 antagonist with high receptor affinity
- C Olanzapine — because it specifically blocks only mesolimbic D2 receptors sparing striatal ones
- D Haloperidol — because of its long half-life reducing peak plasma D2 occupancy
Correct answer: A. Clozapine — because of high D4/5-HT2A receptor affinity and loose, rapidly dissociating D2 binding
Explanation
Clozapine has the lowest EPS and tardive dyskinesia risk among antipsychotics. This is attributed to its preferential limbic vs striatal D2 blockade, its high affinity for D4 and 5-HT2A receptors, and crucially, its loose-binding, fast-dissociation kinetics at D2 receptors (the 'fast-off' theory of Kapur and Seeman). Risperidone has high D2 affinity and causes dose-dependent EPS; haloperidol is a typical antipsychotic with high EPS risk.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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