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 (p=0.0015). Moreover, a significant interaction was found between variants in BDNF and NTRK2, the gene encoding the BNDF receptor (p=0.0003). Among men taking nortriptyline, suicidality was also associated with rs11195419 SNP in the alpha(2A)-adrenergic receptor gene (ADRA2A) (p=0.007). 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.

• Authors: 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
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 34 Issue 12 Pg. 2517-28 (Nov 2009) ISSN: 1740-634X [Electronic] England
• PMID: 19641488 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• ADRA2A protein, human
• Antidepressive Agents
• Brain-Derived Neurotrophic Factor
• Receptors, Adrenergic, alpha-2
• Citalopram
• Nortriptyline
• Receptor, trkB

Topics

• Adult
• Antidepressive Agents (adverse effects, therapeutic use)
• Brain-Derived Neurotrophic Factor (genetics)
• Citalopram (adverse effects, therapeutic use)
• Depressive Disorder, Major (drug therapy, genetics)
• Female
• Follow-Up Studies
• Genetic Predisposition to Disease
• Haplotypes
• Humans
• Linkage Disequilibrium
• Logistic Models
• Male
• Nortriptyline (adverse effects, therapeutic use)
• Polymorphism, Genetic
• Polymorphism, Single Nucleotide
• Receptor, trkB (genetics)
• Receptors, Adrenergic, alpha-2 (genetics)
• Sex Factors
• Suicide