Which receptor-blocking properties of second-generation antipsychotics best explain their propensity to cause significant weight gain?

• A Agonism at serotonin 5-HT1A receptors in the hypothalamus
• B Antagonism at dopamine D2 receptors in the chemoreceptor trigger zone
• C Antagonism at histamine H1 and serotonin 5-HT2C receptors ✓
• D Blockade of muscarinic M1 receptors in the satiety centre

Explanation

Weight gain with agents such as olanzapine and clozapine is attributed chiefly to H1 antagonism, which increases appetite and promotes sedation, combined with 5-HT2A antagonism, which disinhibits hypothalamic appetite regulation. D2 blockade in the chemoreceptor trigger zone produces antiemetic effects rather than weight change, 5-HT1C agonism is not the dominant mechanism, and M1 blockade causes anticholinergic effects such as dry mouth and constipation rather than hyperphagia.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

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