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CYP2D6 pharmacogenomics — MRCPsych Paper A MCQ

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ModerateGeneticsCYP2D6 pharmacogenomicsMRCPsych Paper A

A 30-year-old man develops marked rigidity and bradykinesia after starting low-dose oral risperidone. Plasma testing shows a high concentration of risperidone relative to its active metabolite, 9-hydroxyrisperidone. Pharmacogenomic testing classifies him as a CYP2D6 poor metaboliser. Which pharmacokinetic mechanism best explains this plasma concentration pattern?

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Correct answer: B — Reduced CYP2D6 activity slows conversion of risperidone to 9-hydroxyrisperidone

The correct answer is B. CYP2D6 converts risperidone to 9-hydroxyrisperidone, which is also pharmacologically active. A CYP2D6 poor metaboliser performs this conversion more slowly, producing a higher risperidone concentration and a higher risperidone-to-metabolite ratio. This provides a pharmacokinetic explanation for adverse effects at a low dose, although genotype alone does not prove that it caused the parkinsonism and the combined active fraction may be less markedly altered. CYP3A4 is a secondary metabolic pathway but reduced activity would not accelerate 9-hydroxylation. CYP1A2 is not the principal enzyme responsible for risperidone metabolism. Reduced renal filtration would tend to impair elimination of the active fraction rather than selectively lower 9-hydroxyrisperidone.

Reference: Electronic Medicines Compendium, Risperidone 1 mg/ml oral solution, Summary of Product Characteristics, sections 4.5 and 5.2, updated 14 July 2026. https://www.medicines.org.uk/emc/product/4364/smpc