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

Fabbri, Chiara, Tansey, Katherine, Perlis, Roy H., Hauser, Joanna, Maier, Wolfgang, Mors, Ole, Placentino, Anna, Rietschel, Marcella, Souery, Daniel, Breen, Gerome, Lee, Charles Curtis, Newhouse, Stephen, Patel, Hamel, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Lewis, Glyn, Jenkins, Gregory, Weinshilboum, Richard M., Farmer, Anne, Aitchison, Katherine J., Craig, Ian, McGuffin, Peter, Schruers, Koen, Biernacka, Joanna M., Uher, Rudolf and Lewis, Cathryn M. 2018. Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: meta-analysis of data from genome-wide association studies. European Neuropsychopharmacology 28 (8) , pp. 945-954. 10.1016/j.euroneuro.2018.05.009

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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 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%).

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Neuroscience and Mental Health Research Institute (NMHRI) Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Elsevier
ISSN:	0924-977X
Date of First Compliant Deposit:	17 May 2018
Date of Acceptance:	17 May 2018
Last Modified:	04 Dec 2024 21:00
URI:	https://orca.cardiff.ac.uk/id/eprint/111531

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