Clozapine's superior efficacy in treatment-resistant schizophrenia despite relatively low D2 receptor occupancy is best explained by which property?

• A Highest D2 receptor affinity among all antipsychotics
• B Selective blockade of presynaptic D2 autoreceptors only
• C Potent NMDA receptor antagonism enhancing glutamatergic transmission
• D Faster dissociation from D2 receptors ('hit and run' kinetics) allowing more physiological dopamine signaling ✓

Explanation

Clozapine's unique efficacy is attributed to its 'fast dissociation' or loose binding kinetics at D2 receptors — it transiently occupies and rapidly dissociates from D2 receptors, achieving clinical antipsychotic effect without causing sustained dopamine blockade that leads to EPS or hyperprolactinemia. This 'hit and run' or 'transiently occupying' model (proposed by Seeman and Kapur) also explains why clozapine's superior efficacy coexists with lower (40-60%) D2 occupancy compared to typical antipsychotics (>80%). Clozapine also has multireceptor activity (5-HT2A, M1-5, H1, alpha-1) contributing to its broad efficacy.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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