Clozapine has the lowest risk of extrapyramidal side effects among antipsychotics. The pharmacological basis is:

• A Selective D3 receptor antagonism sparing D2 receptors in striatum
• B Low affinity and fast dissociation from striatal D2 receptors, plus high 5-HT2A antagonism ✓
• C Partial D2 agonism preventing postsynaptic receptor supersensitivity
• D Preferential blockade of limbic D4 receptors over striatal D2 receptors

Explanation

Clozapine's unique EPS-sparing profile results from two complementary mechanisms: (1) it has a relatively low affinity for striatal D2 receptors and dissociates from them rapidly ('fast-off' kinetics), so dopaminergic neurotransmission in the nigrostriatal pathway is minimally disrupted; (2) its potent antagonism of 5-HT2A receptors in the striatum enhances dopamine release, which counterbalances D2 blockade. These properties are shared by other atypical antipsychotics. Aripiprazole uses partial D2 agonism to avoid EPS, but this is not clozapine's mechanism.

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

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