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Ultra-Rapid CYP1A2 and Clozapine — MRCPsych Paper B MCQ

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HardSchizophrenia & PsychosisUltra-Rapid CYP1A2 and ClozapineMRCPsych Paper B

A man with treatment-resistant schizophrenia remains markedly psychotic despite confirmed adherence to clozapine 900 mg daily for an adequate duration. Repeated steady-state trough plasma clozapine concentrations are 0.25 mg/L. His smoking and caffeine intake are stable, interacting enzyme inducers and incorrect sampling have been excluded, and he is tolerating treatment. Specialist assessment supports ultrarapid clozapine metabolism. Which is the most appropriate management option?

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Correct answer: E — Consider a monitored, time-limited trial of clozapine above 900 mg daily, agreed and documented by the multidisciplinary team and the patient

Explanation lettering: C = shown as A · D = shown as B · E = shown as C · A = shown as D · B = shown as E

B is correct. The patient has persistent symptoms and a repeatedly subtherapeutic trough concentration despite the licensed maximum dose, with adherence, sampling problems and reversible pharmacokinetic causes addressed. In a carefully confirmed ultrarapid metaboliser, a dose above 900 mg/day may therefore be considered off-label. NICE requires this to be an agreed, documented, time-limited specialist trial with monitoring of clinical response and adverse effects, including dose-related seizure and cardiovascular risks. Continuing unchanged leaves clozapine unoptimised. Switching discards the antipsychotic with the strongest evidence in treatment-resistant schizophrenia before optimisation has been exhausted. Abrupt cessation risks withdrawal and rebound psychosis, while dose reduction would further lower exposure. Augmentation is generally considered only after clozapine has been optimised, including assessment of therapeutic drug levels.

Reference: National Institute for Health and Care Excellence. Rehabilitation for adults with complex psychosis (NG181), recommendations 1.9.7–1.9.9. 2020. https://www.nice.org.uk/guidance/NG181/chapter/recommendations