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Genetic predictors of response to antidepressants in the GENDEP project

The Pharmacogenomics Journal volume 9, pages 225–233 (2009)Cite this article

Abstract

The objective of the Genome-based Therapeutic Drugs for Depression study is to investigate the function of variations in genes encoding key proteins in serotonin, norepinephrine, neurotrophic and glucocorticoid signaling in determining the response to serotonin-reuptake-inhibiting and norepinephrine-reuptake-inhibiting antidepressants. A total of 116 single nucleotide polymorphisms in 10 candidate genes were genotyped in 760 adult patients with moderate-to-severe depression, treated with escitalopram (a serotonin reuptake inhibitor) or nortriptyline (a norepinephrine reuptake inhibitor) for 12 weeks in an open-label part-randomized multicenter study. The effect of genetic variants on change in depressive symptoms was evaluated using mixed linear models. Several variants in a serotonin receptor gene (HTR2A) predicted response to escitalopram with one marker (rs9316233) explaining 1.1% of variance (P=0.0016). Variants in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants. Two HTR2A markers remained significant after hypothesis-wide correction for multiple testing. A false discovery rate of 0.106 for the three strongest associations indicated that the multiple findings are unlikely to be false positives. The pattern of associations indicated a degree of specificity with variants in genes encoding proteins in serotonin signaling influencing response to the serotonin-reuptake-inhibiting escitalopram, genes encoding proteins in norepinephrine signaling influencing response to the norepinephrine-reuptake-inhibiting nortriptyline and a common pathway gene influencing response to both antidepressants. The single marker associations explained only a small proportion of variance in response to antidepressants, indicating a need for a multivariate approach to prediction.

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Acknowledgements

The GENDEP study was funded by the European Commission Framework 6 grant, EC Contract Ref. LSHB-CT-2003-503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. The Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London and South London and Maudsley NHS Foundation Trust (funded by the National Institute for Health Research, Department of Health, UK) and GlaxoSmithKline contributed by funding add-on projects in the London center. The funders had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the report. We acknowledge the contributions of Andrej Marusic and Jorge Perez, who were the lead investigators at Ljubljana, Slovenia and at Brescia, Italy, and who passed away during the conduct of the study. We also acknowledge the contribution of the following collaborators: Helen Dean, Amanda Elkin, Bhanu Gupta, Cerisse Gunasinghe, Desmond Campbell, Richard J Williamson, David Dempster, Julien Mendlewicz, Maja Bajs, Jana Strohmaier, Christine Schmäl, Susanne Höfels, Anna Schuhmacher, Ute Pfeiffer, Sandra Weber, Anne Schinkel Stamp, Alenka Tancic, Jerneja Sveticic, Zrnka Kovacic, Paweł Kapelski, Maria Skibiñska, Aleksandra Rajewska, Anna Leszczynska, Aleksandra Szczepankiewicz, Elzbieta Cegielska, Laura Pedrini, Cristian Bonvicini, Luciana Rillosi, Sylvie Linotte, Borut Jerman, Tina Žagar and Metka Paragi.

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Author notes

  1. Rudolf Uher and Patricia Huezo-Diaz: These authors contributed equally to this work.

Authors and Affiliations

  1. MRC Social Genetic and Developmental Psychiatry Center, Institute of Psychiatry, King's College London, London, UK

    Rudolf Uher, Patricia Huezo-Diaz, Nader Perroud, Rebecca Smith, Joanna M Gray, Cathryn M Lewis, Anne Farmer, Katherine J Aitchison, Peter McGuffin & Ian Craig

  2. Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany

    Marcella Rietschel & Thomas G Schulze

  3. Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark

    Ole Mors

  4. Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland

    Joanna Hauser & Piotr M Czerski

  5. Department of Psychiatry, University of Bonn, Bonn, Germany

    Wolfgang Maier & Astrid Zobel

  6. Preventive Unit CINDI, Community Health Center Ljubljana, Ljubljana, Slovenia

    Dejan Kozel

  7. Department of Neuropharmacology and Behavioural Pharmacology, Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia

    Neven Henigsberg & Petra Kalember

  8. Department of Psychiatry, Université Libre de Bruxelles, Erasme Academic Hospital, Brussels, Belgium

    Mara Barreto

  9. Department of Psychiatry, Biological Psychiatry Unit and Dual Diagnosis Ward, Istituto di Ricovero e Cura a Carattere Scientifico Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy

    Anna Placentino & Caterina Giovannini

  10. Educational and Research Institute Ozara, Ljubljana, Slovenia

    Mojca Zvezdana Dernovsek

  11. Clinic for Chronic Depression, Aarhus Univeristy Hospital, Risskov, Denmark

    Erik Roj Larsen

  12. Laboratoire de Psychologie Médicale, Université Libre de Bruxelles and Psy Pluriel-Centre Européen de Psychologie Médicale, Belgium

    Daniel Souery

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Correspondence to Rudolf Uher.

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Supplementary Information accompanies the paper on The Pharmacogenomics Journal website (http://www.nature.com/tpj)

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Uher, R., Huezo-Diaz, P., Perroud, N. et al. Genetic predictors of response to antidepressants in the GENDEP project. Pharmacogenomics J 9, 225–233 (2009). https://doi.org/10.1038/tpj.2009.12

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