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 journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Chiara Fabbri, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 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.
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  • Katherine E Tansey, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom.
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  • Roy H Perlis, Department of Psychiatry, Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Boston, USA.
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  • Joanna Hauser, Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
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  • Neven Henigsberg, Croatian Institute for Brain Research, Medical School, University of Zagreb, Salata 3, 10 000, Zagreb, Croatia.
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  • Wolfgang Maier, Department of Psychiatry, University of Bonn, Bonn, Germany.
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  • Ole Mors
  • Anna Placentino, Biological Psychiatry Unit and Dual Diagnosis Ward, Istituto Di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy.
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  • Marcella Rietschel, Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
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  • Daniel Souery, aa Laboratoire de Psychologie Medicale, Centre Européen de Psychologie Medicale , Université Libre de Bruxelles and Psy Pluriel , Brussels , Belgium.
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  • Gerome Breen, 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.
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  • Charles Curtis, 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.
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  • Sang-Hyuk Lee, 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.
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  • Stephen Newhouse, 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.
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  • Hamel Patel, 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.
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  • Michael O'Donovan, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, United Kingdom; Neuroscience and Mental Health Research Institute, Cardiff University, United Kingdom.
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  • Glyn Lewis, Division of Psychiatry, University College London (UCL), London, United Kingdom.
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  • Gregory Jenkins, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
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  • Richard M Weinshilboum, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
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  • Anne Farmer, 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.
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  • Katherine J Aitchison, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK; Department of Psychiatry and Medical Genetics, University of Alberta, 116 St and 85 Ave, Edmonton, AB, T6G 2R3, Canada.
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  • Ian Craig, 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.
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  • Peter McGuffin, 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.
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  • Koen Schruers, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands.
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  • Joanna M Biernacka, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, United States.
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  • Rudolf Uher, Department of Psychiatry, Dalhousie University, Halifax, N.S., Canada.
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  • Cathryn M Lewis, 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. Electronic address: cathryn.lewis@kcl.ac.uk.
  • Centre for Psychiatric Research

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%).

Original languageEnglish
JournalEuropean neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
Volume28
Issue8
Pages (from-to)945-954
Number of pages10
ISSN0924-977X
DOIs
Publication statusPublished - Aug 2018

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