Clozapine has the lowest risk of tardive dyskinesia among antipsychotics despite being highly efficacious in refractory schizophrenia. Which pharmacological property best explains this?
- A Clozapine has higher D2 receptor occupancy than haloperidol
- B Clozapine is a 'fast-off' D2 antagonist (loose binding) with high 5-HT2A antagonism and lower striatal D2 occupancy (60–70%) ✓
- C Clozapine preferentially blocks D3 receptors in the limbic system
- D Clozapine lacks affinity for D2 receptors and acts solely through serotonin antagonism
Correct answer: B. Clozapine is a 'fast-off' D2 antagonist (loose binding) with high 5-HT2A antagonism and lower striatal D2 occupancy (60–70%)
Explanation
Clozapine's unique pharmacodynamic profile includes 'fast-off' binding kinetics at D2 receptors (rapid dissociation from D2), resulting in only 60–70% D2 occupancy in the striatum at therapeutic doses (versus >80% for typical antipsychotics). This spares nigrostriatal D2 receptors, reducing EPS and tardive dyskinesia. Its potent 5-HT2A antagonism in cortical and striatal regions also modulates dopaminergic activity. Option A is incorrect; C is partially true but not the main reason; D is incorrect as clozapine does have D2 affinity.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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