A 28-year-old man with major depressive disorder is started on an SSRI but shows no response after 8 weeks at adequate dose. Genetic testing reveals he is a CYP2D6 ultra-rapid metabolizer. Which statement best explains his pharmacokinetic situation and guides the next therapeutic step?

• A Ultra-rapid CYP2D6 metabolism causes excessive conversion of the SSRI to toxic metabolites, explaining treatment failure
• B CYP2D6 ultra-rapid metabolism accelerates clearance of SSRIs metabolized by CYP2D6 (e.g., fluoxetine, paroxetine), resulting in subtherapeutic plasma levels and treatment failure; switching to an SSRI not metabolized by CYP2D6 (e.g., escitalopram/citalopram) or using higher doses is appropriate ✓
• C CYP2D6 ultra-rapid metabolizers should never receive SSRIs and require immediate TCA therapy
• D The genetic variant increases drug absorption, not metabolism, and serum drug levels would be elevated despite the genetic polymorphism

Explanation

CYP2D6 ultra-rapid metabolizers (UMs) carry multiple functional copies of the CYP2D6 gene and have markedly increased enzyme activity. SSRIs like fluoxetine, paroxetine, and fluvoxamine are substrates (and inhibitors) of CYP2D6. In UMs, these drugs are cleared much faster, leading to lower-than-expected plasma concentrations at standard doses and potentially inadequate antidepressant effect. The solution is either to switch to an SSRI primarily metabolized by CYP3A4 or CYP2C19 (escitalopram, sertraline) or to use higher doses with therapeutic drug monitoring. This is a clinically relevant pharmacogenomic application endorsed by CPIC guidelines.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.