A patient on clozapine develops fever, tachycardia, diaphoresis, extrapyramidal rigidity, and a creatine kinase of 12,000 U/L. The treating physician suspects neuroleptic malignant syndrome (NMS). Paradoxically, clozapine causes NMS through which mechanism despite its low D2 binding affinity?
- A High 5-HT2A antagonism triggering serotonin toxicity
- B Anticholinergic-induced hyperthermia and autonomic instability
- C Dopaminergic withdrawal effect from rapid dose reduction or abrupt cessation ✓
- D Alpha-1 blockade causing severe hypotension and compensatory rigidity
Explanation
Although clozapine has very low D2 receptor affinity (explaining its low EPS profile), NMS can occur — paradoxically most commonly triggered by abrupt clozapine withdrawal or rapid dose reduction rather than initiation. Sudden removal of even weak D2 blockade/dopaminergic modulation from an adapted system precipitates severe dopaminergic deficiency in the basal ganglia and hypothalamus. Serotonin toxicity (option A) is a distinct syndrome with hyperreflexia and clonus, not rigidity. Anticholinergic effects cause hyperthermia but not the full NMS triad with rigidity/elevated CK. Alpha-1 blockade is a side effect of clozapine but doesn't cause NMS.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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