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

By Chiara Fabbri, Katherine E Tansey, Roy H Perlis, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Gerome Breen, Charles Curtis, Sang-Hyuk Lee, Stephen Newhouse, Hamel Patel, Michael O’Donovan, Glyn Lewis, Gregory Jenkins, Richard M Weinshilboum, Anne Farmer, Katherine J Aitchison, Ian Craig, Peter McGuffin, Koen Schruers, Joanna M Biernacka, Rudolf Uher, Cathryn M Lewis

Posted 06 Feb 2018
bioRxiv DOI: 10.1101/259838 (published DOI: 10.1016/j.euroneuro.2018.05.009)

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 how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 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 common CYP2C19 functional 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 percentage symptom improvement and remission. Side effect data were available at weeks 2-4, 6 and 9 in three of the investigated 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 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 among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs are relatively rare among Caucasians (~2%).

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