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Fluvoxamine-Clozapine Interaction — MRCPsych Paper B MCQ

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HardSchizophrenia & PsychosisFluvoxamine-Clozapine InteractionMRCPsych Paper B

A 40-year-old man with treatment-resistant schizophrenia has taken clozapine 400 mg daily at an unchanged dose for 6 months. He smokes 15 cigarettes daily and reports no change in smoking, caffeine intake, adherence or physical health. Fluvoxamine 50 mg daily is added for comorbid obsessive–compulsive disorder. Two weeks later he is markedly sedated. His pre-dose clozapine concentration has risen from 0.45 mg/L to 1.20 mg/L, with an increased clozapine-to-norclozapine ratio. Which pharmacokinetic mechanism best explains this pattern?

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Correct answer: B — Inhibition of CYP1A2-mediated hepatic metabolism of clozapine

Fluvoxamine is a strong CYP1A2 inhibitor. CYP1A2 is clinically important in clozapine metabolism, including its N-demethylation to norclozapine. Inhibition reduces clozapine clearance, increasing the parent-drug concentration and usually the clozapine-to-norclozapine ratio. The unchanged dose and absence of changes in smoking, caffeine intake or physical health support this interaction; sedation is consistent with the raised clozapine exposure. Only trace unchanged clozapine is renally excreted, so renal tubular competition is not responsible. CYP3A4 induction would tend to lower clozapine concentrations. Intestinal P-glycoprotein inhibition is not the established principal mechanism, while protein-binding displacement would not explain this sustained increase in total pre-dose concentration and altered metabolite ratio.

Reference: electronic Medicines Compendium, Faverin 50 mg Film-coated Tablets, Summary of Product Characteristics, section 4.5: Interaction with other medicinal products and other forms of interaction, updated 5 March 2026. https://www.medicines.org.uk/emc/product/1169/smpc