A patient homozygous for CYP2C19*17 alleles (ultrarapid metabolizer) is started on escitalopram for depression. Compared to an extensive metabolizer, what is most likely to occur?
- A Accumulation of S-citalopram's active metabolite S-desmethylcitalopram causing serotonin syndrome
- B Competitive inhibition of CYP2C19 by escitalopram in ultrarapid metabolizers, normalizing drug levels
- C Reduced escitalopram plasma levels leading to subtherapeutic response and likely need for dose escalation ✓
- D Enhanced conversion to R-citalopram increasing CNS side effects
Explanation
Escitalopram (S-citalopram) is a major substrate of CYP2C19. The CYP2C19*17 allele is a gain-of-function variant creating increased enzyme expression. Homozygous *17/*17 individuals are ultrarapid metabolizers who clear escitalopram much faster than extensive metabolizers, resulting in significantly reduced plasma concentrations and likely inadequate antidepressant effect. FDA and CPIC guidelines now recommend considering higher doses or alternative SSRIs less dependent on CYP2C19 (e.g., sertraline, which relies more on CYP2C19 but less dramatically; or fluvoxamine). The primary metabolite S-desmethylcitalopram has less pharmacological activity. This pharmacogenomic interaction is clinically significant and measurable with commercial testing.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.