A 28-year-old man with a 2-year history of schizophrenia on clozapine develops progressive cognitive slowing and seizures. His clozapine serum level is 1100 ng/mL (therapeutic: 350–600 ng/mL). Which metabolic pathway is primarily responsible for clozapine toxicity at high plasma levels?

• A CYP1A2 saturation leading to accumulation of norclozapine ✓
• B CYP3A4 induction causing increased toxic metabolite formation
• C CYP2D6 inhibition by smoking cessation raising plasma levels
• D Glucuronidation failure leading to direct clozapine accumulation

Explanation

Clozapine is primarily metabolized by CYP1A2. Smoking induces CYP1A2; smoking cessation (common in hospitalized patients) reduces CYP1A2 activity, leading to clozapine and norclozapine accumulation. The toxic metabolite norclozapine accumulates when CYP1A2 is saturated or inhibited, contributing to seizures. Routine clozapine level monitoring is mandatory, especially during changes in smoking habits, intercurrent illness (fever reduces CYP1A2), or addition of ciprofloxacin (CYP1A2 inhibitor).

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

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