Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project

Nader Perroud; Katherine J. Aitchison; Rudolf Uher; Rebecca Smith; Patricia Huezo-Diaz; Andrej Marusic; Wolfgang Maier; Ole Mors; Anna Placentino; Neven Henigsberg; Marcella Rietschel; Joanna Hauser; Daniel Souery; Pawel Kapelski; Cristian Bonvicini; Astrid Zobel; Lisbeth Jorgensen; Ana Petrovic; Petra Kalember; Thomas G. Schulze; Bhanu Gupta; Joanna Gray; Cathryn M. Lewis; Anne E. Farmer; Peter McGuffin; Ian Craig

doi:10.1038/npp.2009.81

Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project

Nader Perroud, Katherine J. Aitchison, Rudolf Uher, Rebecca Smith, Patricia Huezo-Diaz, Andrej Marusic, Wolfgang Maier, Ole Mors, Anna Placentino, Neven Henigsberg, Marcella Rietschel, Joanna Hauser, Daniel Souery, Pawel Kapelski, Cristian Bonvicini, Astrid Zobel, Lisbeth Jorgensen, Ana Petrovic, Petra Kalember, Thomas G. SchulzeBhanu Gupta, Joanna Gray, Cathryn M. Lewis, Anne E. Farmer, Peter McGuffin, Ian Craig

Research output: Contribution to journal › Article › peer-review

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Abstract

The aim of this study was to investigate genetic predictors of an increase in suicidal ideation during treatment with a selective serotonin reuptake inhibitor or a tricyclic antidepressant. A total of 796 adult patients with major depressive disorder who were treated with a flexible dosage of escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP) were included in the sample and provided data on suicidal ideation. Nine candidate genes involved in neurotrophic, serotonergic, and noradrenergic pathways were selected based on previous association studies with suicidal ideation or behavior. Using a logistic regression model, 123 polymorphisms in these genes were compared between subjects with an increase in suicidal ideation and those without any increase in suicidal ideation. Polymorphisms in BDNF, the gene encoding the brain-derived neurotrophic factor, were significantly associated with an increase in suicidal ideation. The strongest association was observed for rs962369 in BDNF (p0.0015). Moreover, a significant interaction was found between variants in BDNF and NTRK2, the gene encoding the BNDF receptor (p0.0003). Among men taking nortriptyline, suicidality was also associated with rs11195419 SNP in the alpha 2A-adrenergic receptor gene (ADRA2A) (p0.007). The associations observed with polymorphisms in BDNF suggest the involvement of the neurotrophic system in vulnerability to suicidality. Epistasis between BDNF and NTRK2 suggests that genetic variations in the two genes are involved in the same causal mechanisms leading to suicidality during antidepressant treatment. Among men, genetic variation in noradrenergic signaling may interact with norepinephrine reuptake-inhibiting antidepressants, thereby contributing to suicidality.

Original language	English
Pages (from-to)	2517-2528
Number of pages	12
Journal	Neuropsychopharmacology
Volume	34
Issue number	12
DOIs	https://doi.org/10.1038/npp.2009.81
Publication status	Published - Nov 2009
Externally published	Yes

Bibliographical note

Funding Information:
The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Nader Perroud was founded by the Swiss National Science foundation: PASMA-118605. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline contributed by funding an add-on project in the London center. In its latter stages, GENDEP received additional funding at the Institute of Psychiatry site from the Biomedical Research Center for Mental Health at the Institute of Psychiatry, King’s College London and South London, and Maudsley NHS Foundation Trust (National Institute for Health Research, Department of Health, UK). However, the authors work was independent of the funders, with the legal sponsor of the study being the Institute of Psychiatry at King’s College London. The funders had no role in the design and conduct of the study, in data collection, analysis, interpretation, or writing of this report.

ASJC Scopus Subject Areas

Pharmacology
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/npp.2009.81

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Perroud, N., Aitchison, K. J., Uher, R., Smith, R., Huezo-Diaz, P., Marusic, A., Maier, W., Mors, O., Placentino, A., Henigsberg, N., Rietschel, M., Hauser, J., Souery, D., Kapelski, P., Bonvicini, C., Zobel, A., Jorgensen, L., Petrovic, A., Kalember, P., ... Craig, I. (2009). Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project. Neuropsychopharmacology, 34(12), 2517-2528. https://doi.org/10.1038/npp.2009.81

Perroud, N, Aitchison, KJ, Uher, R, Smith, R, Huezo-Diaz, P, Marusic, A, Maier, W, Mors, O, Placentino, A, Henigsberg, N, Rietschel, M, Hauser, J, Souery, D, Kapelski, P, Bonvicini, C, Zobel, A, Jorgensen, L, Petrovic, A, Kalember, P, Schulze, TG, Gupta, B, Gray, J, Lewis, CM, Farmer, AE, McGuffin, P & Craig, I 2009, 'Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project', Neuropsychopharmacology, vol. 34, no. 12, pp. 2517-2528. https://doi.org/10.1038/npp.2009.81

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title = "Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project",

abstract = "The aim of this study was to investigate genetic predictors of an increase in suicidal ideation during treatment with a selective serotonin reuptake inhibitor or a tricyclic antidepressant. A total of 796 adult patients with major depressive disorder who were treated with a flexible dosage of escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP) were included in the sample and provided data on suicidal ideation. Nine candidate genes involved in neurotrophic, serotonergic, and noradrenergic pathways were selected based on previous association studies with suicidal ideation or behavior. Using a logistic regression model, 123 polymorphisms in these genes were compared between subjects with an increase in suicidal ideation and those without any increase in suicidal ideation. Polymorphisms in BDNF, the gene encoding the brain-derived neurotrophic factor, were significantly associated with an increase in suicidal ideation. The strongest association was observed for rs962369 in BDNF (p0.0015). Moreover, a significant interaction was found between variants in BDNF and NTRK2, the gene encoding the BNDF receptor (p0.0003). Among men taking nortriptyline, suicidality was also associated with rs11195419 SNP in the alpha 2A-adrenergic receptor gene (ADRA2A) (p0.007). The associations observed with polymorphisms in BDNF suggest the involvement of the neurotrophic system in vulnerability to suicidality. Epistasis between BDNF and NTRK2 suggests that genetic variations in the two genes are involved in the same causal mechanisms leading to suicidality during antidepressant treatment. Among men, genetic variation in noradrenergic signaling may interact with norepinephrine reuptake-inhibiting antidepressants, thereby contributing to suicidality.",

author = "Nader Perroud and Aitchison, {Katherine J.} and Rudolf Uher and Rebecca Smith and Patricia Huezo-Diaz and Andrej Marusic and Wolfgang Maier and Ole Mors and Anna Placentino and Neven Henigsberg and Marcella Rietschel and Joanna Hauser and Daniel Souery and Pawel Kapelski and Cristian Bonvicini and Astrid Zobel and Lisbeth Jorgensen and Ana Petrovic and Petra Kalember and Schulze, {Thomas G.} and Bhanu Gupta and Joanna Gray and Lewis, {Cathryn M.} and Farmer, {Anne E.} and Peter McGuffin and Ian Craig",

note = "Funding Information: The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Nader Perroud was founded by the Swiss National Science foundation: PASMA-118605. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline contributed by funding an add-on project in the London center. In its latter stages, GENDEP received additional funding at the Institute of Psychiatry site from the Biomedical Research Center for Mental Health at the Institute of Psychiatry, King{\textquoteright}s College London and South London, and Maudsley NHS Foundation Trust (National Institute for Health Research, Department of Health, UK). However, the authors work was independent of the funders, with the legal sponsor of the study being the Institute of Psychiatry at King{\textquoteright}s College London. The funders had no role in the design and conduct of the study, in data collection, analysis, interpretation, or writing of this report.",

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T1 - Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project

AU - Perroud, Nader

AU - Aitchison, Katherine J.

AU - Uher, Rudolf

AU - Smith, Rebecca

AU - Huezo-Diaz, Patricia

AU - Marusic, Andrej

AU - Maier, Wolfgang

AU - Mors, Ole

AU - Placentino, Anna

AU - Henigsberg, Neven

AU - Rietschel, Marcella

AU - Hauser, Joanna

AU - Souery, Daniel

AU - Kapelski, Pawel

AU - Bonvicini, Cristian

AU - Zobel, Astrid

AU - Jorgensen, Lisbeth

AU - Petrovic, Ana

AU - Kalember, Petra

AU - Schulze, Thomas G.

AU - Gupta, Bhanu

AU - Gray, Joanna

AU - Lewis, Cathryn M.

AU - Farmer, Anne E.

AU - McGuffin, Peter

AU - Craig, Ian

N1 - Funding Information: The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Nader Perroud was founded by the Swiss National Science foundation: PASMA-118605. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline contributed by funding an add-on project in the London center. In its latter stages, GENDEP received additional funding at the Institute of Psychiatry site from the Biomedical Research Center for Mental Health at the Institute of Psychiatry, King’s College London and South London, and Maudsley NHS Foundation Trust (National Institute for Health Research, Department of Health, UK). However, the authors work was independent of the funders, with the legal sponsor of the study being the Institute of Psychiatry at King’s College London. The funders had no role in the design and conduct of the study, in data collection, analysis, interpretation, or writing of this report.

PY - 2009/11

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N2 - The aim of this study was to investigate genetic predictors of an increase in suicidal ideation during treatment with a selective serotonin reuptake inhibitor or a tricyclic antidepressant. A total of 796 adult patients with major depressive disorder who were treated with a flexible dosage of escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP) were included in the sample and provided data on suicidal ideation. Nine candidate genes involved in neurotrophic, serotonergic, and noradrenergic pathways were selected based on previous association studies with suicidal ideation or behavior. Using a logistic regression model, 123 polymorphisms in these genes were compared between subjects with an increase in suicidal ideation and those without any increase in suicidal ideation. Polymorphisms in BDNF, the gene encoding the brain-derived neurotrophic factor, were significantly associated with an increase in suicidal ideation. The strongest association was observed for rs962369 in BDNF (p0.0015). Moreover, a significant interaction was found between variants in BDNF and NTRK2, the gene encoding the BNDF receptor (p0.0003). Among men taking nortriptyline, suicidality was also associated with rs11195419 SNP in the alpha 2A-adrenergic receptor gene (ADRA2A) (p0.007). The associations observed with polymorphisms in BDNF suggest the involvement of the neurotrophic system in vulnerability to suicidality. Epistasis between BDNF and NTRK2 suggests that genetic variations in the two genes are involved in the same causal mechanisms leading to suicidality during antidepressant treatment. Among men, genetic variation in noradrenergic signaling may interact with norepinephrine reuptake-inhibiting antidepressants, thereby contributing to suicidality.

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Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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