A patient on clozapine develops severe metabolic syndrome. The receptor most responsible for clozapine-induced weight gain and hyperphagia is:
- A D2 dopamine receptor antagonism in the nucleus accumbens reducing reward-driven eating
- B H1 histamine receptor antagonism in the hypothalamus, reducing satiety signalling and promoting appetite ✓
- C 5-HT2C serotonin receptor agonism in the arcuate nucleus
- D Muscarinic M3 receptor antagonism causing reduced GLP-1 secretion from L-cells
Explanation
Clozapine's potent H1 histamine receptor antagonism in the hypothalamic arcuate nucleus and ventromedial nucleus impairs histamine's normal role in inhibiting food intake and promoting satiety, leading to hyperphagia and significant weight gain. This is the dominant mechanism for antipsychotic-induced weight gain, and drugs with high H1 affinity (clozapine, olanzapine) cause the most weight gain. Additionally, 5-HT2C antagonism (not agonism) contributes by reducing satiety. M3 antagonism causes dry mouth and constipation but does not significantly alter GLP-1. D2 blockade does not promote weight gain directly.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.