A patient with treatment-resistant schizophrenia develops a serum glucose of 310 mg/dL with polydipsia and polyuria after 8 months on clozapine. The mechanism most responsible for this metabolic complication is:

• A Blockade of dopamine D2 receptors in the hypothalamus
• B Alpha-1 adrenergic blockade reducing hepatic gluconeogenesis
• C Direct pancreatic beta-cell toxicity via muscarinic M3 agonism
• D Antagonism of histamine H1 and serotonin 5-HT2C receptors leading to increased appetite, weight gain, and insulin resistance ✓

Explanation

Clozapine causes metabolic syndrome primarily through potent H1 histamine and 5-HT2C receptor antagonism, which drives hyperphagia, weight gain, dyslipidaemia, and insulin resistance. Additionally, clozapine's muscarinic M3 receptor antagonism in the pancreas reduces insulin secretion, compounding hyperglycaemia. D2 blockade is not the primary metabolic driver.

Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.

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