Longitudinal impact of CYP2D6 and CYP2C19 metabolizer status on antidepressant response: The role of Pharmacogenetic mismatch

Background Pharmacogenetic (PGx) guidance for antidepressants focuses on cytochrome (CYP) 2D6 and 2C19, yet real-world evidence on clinically mismatched prescriptions i.e., drugs whose metabolism is not concordant with a patient's PGx phenotype, remains limited. Methods In this 12-week prospective study we genotyped 244 outpatients with major depressive disorder (MDD) and classified their current antidepressant as CYP mismatch ( n = 114, 46.7 %) or no mismatch ( n = 130, 53.3 %). Longitudinal change in Hamilton Depression Rating Scale (HAM-D) percentage improvement was analysed with a mixed-effects model. Safety was assessed with the Udvalg for Kliniske Undersøgelser (UKU) scale. Results The primary model showed a detrimental effect of mismatch on HAM-D improvement (β = −14.65 ± 7.42 %, p = 0.048) and a non-significant trend for time × mismatch interaction (β = 1.30 ± 0.76 %/week, p = 0.088). By week 12, mean improvement was 59.3 ± 25.6 % in the no-mismatch group versus 54.9 ± 28.8 % in mismatch. Overall response (32.1 % vs 37.9 %, p = 0.46) and remission rates (43.8 % vs 50.5 %, p = 0.39) did not differ. Conversely, UKU global scores were significantly higher in mismatch both at week 8 (1.43 ± 1.23 vs 1.07 ± 1.16, p = 0.025) and week 12 (1.03 ± 1.16 vs 0.72 ± 1.09, p = 0.048). Conclusions While categorical response and remission rates did not differ between groups and numerically favored the mismatch group, side-effect burden was modestly higher with mismatch; continuous trajectories nevertheless showed a small but consistent disadvantage associated with mismatch.