Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies

摘要

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate howCYP2C19polymorphisms predict citalopram/escitalopram efficacy and side effects.CYP2C19metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most commonCYP2C19functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2–4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group.Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD?=?0.43, CI?=?0.19–0.66) and higher remission rates (OR?=?1.55, CI?=?1.23–1.96) compared to EMs. At weeks 2–4, PMs showed higher risk of gastro-intestinal (OR?=?1.26, CI?=?1.08–1.47), neurological (OR?=?1.28, CI?=?1.07–1.53) and sexual side effects (OR?=?1.52, CI?=?1.23–1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different amongCYP2C19groups.CYP2C19polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (～2%).