Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies |
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| Authors: | 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,Stephen Newhouse,Hamel Patel,Michael O&#x Donovan,Glyn Lewis,Gregory Jenkins,Cathryn M. Lewis |
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| Affiliation: | 1. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy;2. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King''s College London, PO80, De De Crespigny Park, Denmark Hill United Kingdom;3. College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom;4. Department of Psychiatry, Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Boston, USA;5. Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland;6. Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia;g. Department of Psychiatry, University of Bonn, Bonn, Germany;h. Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark;i. Biological Psychiatry Unit and Dual Diagnosis Ward, Istituto Di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy;j. Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany;k. Laboratoire de Psychologie Médicale, Université Libre de Bruxelles and Psy Pluriel—Centre Européen de Psychologie Médicale, Brussels, Belgium;l. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom;m. Division of Psychiatry, University College London (UCL), London, United Kingdom;n. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;o. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA;p. Department of Psychiatry, University of Alberta, Edmonton, AB, Canada;q. School of Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands;r. Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, United States;s. Department of Psychiatry, Dalhousie University, Halifax, Canada |
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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 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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| Keywords: | Gene Antidepressant Response Side effects Major depression |
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