Effect of Individual and Combined Cytochrome P450 Activity Scores on Symptom Improvement and Side Effects in Youth Treated With Sertraline.

Sertraline is commonly used to treat mental health conditions in youth. However, its tolerability and efficacy vary between individuals, partly due to interindividual differences in drug metabolism. This study assessed the individual and combined impact of genetic variation in cytochrome P450 drug-metabolizing enzymes on patient-reported side effects and symptom improvement in 347 youth, aged 6-24, receiving sertraline treatment. Participants reported sertraline dose, duration, adherence, concomitant medications, side effects, and symptom improvement. DNA was extracted from saliva samples and genotyped for CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Individual activity scores and a weighted combinatorial CYP450 activity score were created. Binomial logistic regression models were used to assess the impact individual and combined CYP450 activity scores had on patient-reported side effects and symptom improvement, both with and without correction for phenoconversion. After adjusting for phenoconversion, other CYP450 activity scores, and covariates, higher activity scores for CYP2D6 (OR = 0.288, 95% CI = 0.091-0.913) and CYP3A4 (OR = 0.002, 95% CI = 0.001-0.375) were nominally associated with reduced odds of symptom improvement. A higher combined CYP450 activity score was associated with reduced odds of symptom improvement (OR = 0.060, 95% CI = 0.004-0.797) and side effects (OR = 0.097, 95% CI = 0.010-0.925). These findings suggest that a combined CYP450 activity score may serve as a marker of symptom improvement and side effects in youth, but validation using sertraline/desmethylsertraline concentrations is required. If validated, these results may inform updates to pharmacogenetic prescribing guidelines for sertraline and support more personalized sertraline use in youth.