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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

Research output: Contribution to journalArticle

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 & 7 others Katherine J. Aitchison, Ian Craig, Peter McGuffin, Koen Schruers, Joanna M. Biernacka, Rudolf Uher, Cathryn M. Lewis

Original languageEnglish
JournalEuropean Neuropsychopharmacology
Early online date28 Jun 2018
DOIs
StateE-pub ahead of print - 28 Jun 2018

King's Authors

Abstract

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 metabolic 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 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 among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).

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