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Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project

The Pharmacogenomics Journal volume 11, pages 138–145 (2011)Cite this article

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Abstract

There is substantial inter-individual variation in response to antidepressants, and genetic variation may, in part, explain these differences. For example, there is evidence to suggest that variation in the serotonin transporter gene (SLC6A4) predicts response to selective serotonin reuptake inhibitors (SSRIs). Environmental factors such as the occurrence of stressful life events before treatment may also be important. One prior report suggests that both factors interact in predicting response to antidepressants. GENDEP, a prospective part-randomized pharmacogenomics trial, collected longitudinal data on the outcome of 811 patients with major depression undergoing treatment with either an SSRI (escitalopram) or a tricyclic antidepressant (nortriptyline). Life events experienced over 6 months preceding treatment were measured using a List of Threatening Experiences Questionnaire, and several polymorphisms in the serotonin transporter gene (SLC6A4) have been genotyped including the serotonin transporter-linked polymorphic region (5-HTTLPR). Stressful life events were shown to predict a significantly better response to escitalopram but had no effect on response to nortriptyline. Variation in the 5-HTTLPR and another polymorphism in the gene, STin4, significantly modified these effects. Gene–environment interactions including life events may therefore be important not only in the aetiology of depression, but also in predicting response to antidepressant medication.

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Acknowledgements

We acknowledge the contribution of the following collaborators: Helen Dean, Amanda Elkin, Joanna Gray, Cerisse Gunasinghe, Desmond Campbell, David Dempster, Richard J Williamson, Caterina Giovannini, Julien Mendlewicz, Thomas Schulze, Jana Strohmaier, Christine Schmäl, Susanne Höfels, Anna Schuhmacher, Ute Pfeiffer, Sandra Weber, Anne Schinkel Stamp, Piotr Czerski Alenka Tancic, Jerneja Sveticic, Zrnka Kovacic, Paweł Kapelski, Maria Skibińska, Aleksandra Rajewska, Aleksandra Szczepankiewicz and Elzbieta Cegielska. We specially acknowledge the contribution of Jorge Perez, who was the Principal Investigator at Brescia, Italy, and who passed away in October 2007, and the late Professor Andrej Marusic, who was the Lead Investigator at Ljubljana, and who passed away in June 2008. The GENDEP project 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. GlaxoSmithKline, the Medical Research Council, the Biomedical Research Center for Mental Health at the Institute of Psychiatry and South London and Maudsley NHS Foundation Trust (funded by the United Kingdom National Institute for Health Research of the Department of Health) contributed to the funding of the sample collection at the Institute of Psychiatry, London, through add-on projects or latterly staff funding. The sponsors had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the paper.

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Authors and Affiliations

  1. MRC SGDP, Institute of Psychiatry, King's College London, London, UK

    R Keers, R Uher, P Huezo-Diaz, R Smith, S Jaffee, B Gupta, F Hoda, I Craig, P McGuffin, A E Farmer & K J Aitchison

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

    M Rietschel

  3. Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia

    N Henigsberg

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

    D Kozel

  5. Center for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark

    O Mors & E R Larsen

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

    W Maier & A Zobel

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

    J Hauser & M Dmitrzak-Weglarz

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

    D Souery

  9. Biological Psychiatry Unit and Dual Diagnosis ward IRCCS, Centro San Giovanni di Dio, FBF, Brescia, Italy

    A Placentino

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  1. R Keers
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Correspondence to R Keers.

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Competing interests

Keers, Uher, Huezo-Diaz, Smith, Jaffee, Rietschel, Kozel, Mors, Maier, Hauser, Placentino, Zobel, Larsen, Czerski, Gupta, Hoda and Craig report no competing interests. Henigsberg and Souery participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. Aitchison, Farmer and McGuffin have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies including Lundbeck and GlaxoSmithKline.

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Keers, R., Uher, R., Huezo-Diaz, P. et al. Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project. Pharmacogenomics J 11, 138–145 (2011). https://doi.org/10.1038/tpj.2010.14

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