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

作者：Alessandro Serretti, Sergio Barlati, Lisa Buson, Valentina Menesello, Anna Magistrali, Rosana Carvalho Silva, Giulia Perusi, Gabriele Nibbio, Stefano Bignotti, G.B. Tura, Antonio Vita, Raffaele Ferri, Chiara Fabbri, Massimo Gennarelli, Alessandra Minelli · 发表于：Journal of Affective Disorders · 年份：2025 · DOI：10.1016/j.jad.2025.120724 · 被引用次数：1 · 研究领域：Pharmacogenetics and Drug Metabolism、Treatment of Major Depression、Eicosanoids and Hypertension Pharmacology

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. 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. 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). 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 b...