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 ¼ 0.0015). Moreover, a significant interaction was found between variants in BDNF and NTRK2, the gene encoding the BNDF receptor (p ¼ 0.0003). Among men taking nortriptyline, suicidality was also associated with rs11195419 SNP in the alpha 2A -adrenergic receptor gene (ADRA2A) (p ¼ 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.

Is it valid to measure suicidal ideation by depression rating scales?

“…In clinical practice, although the Hamilton Depression Rating Scale (HAM-D) was developed for use with psychiatric inpatients diagnosed with unipolar and bipolar affective disorder, it became the most common scale used in treatment trials on depressed outpatients (Bagby et al, 2004;Elkin et al, 1989) and is widely used for clinical evaluation of patients arriving in a psychiatric emergency setting, at least in Europe. A couple of recent pharmacogenetic studies used the 'suicide' item of Hamilton's, Beck's or Montgomery-Asberg's depressive scale in order to assess the suicidal ideations associated with antidepressant treatment in the context of clinical trials (Perroud, 2011;Perroud et al, 2009aPerroud et al, , 2009bPerroud et al, , 2010. However, there is no direct evidence that a single item 'suicide' correlates with a gold standard clinical evaluation of suicide ideation such as the score at the Beck's Scale for Suicide Ideation (SSI) (Beck et al, 1979).…”

Predicting White Matter Integrity from Multiple Common Genetic Variants

“…We did not find evidence for two-way interactions between the SNPs in our study, which is probably reasonable, as the SNPs are likely contributing independently and additively to white matter integrity, and interactions are second-order effects (modulations of the main effect of a gene) that may require large samples to identify, if present at all. Such interactions, however, may be identified in follow-up studies particularly with SNPs that directly share the same pathway, like NTRK2 and BDNF (Perroud et al, 2009), NRG1 and ErbB4 (Nicodemus et al, 2010), or COMT and 5-HTTLPR (Borroni et al, 2006). In this paper, we took a voxelwise approach to study genetic associations with FA.…”

Pharmacogenetics of antidepressant drugs: An update

“…However, another study failed to confirm the relevance of this gene in modulating the response to citalopram treatment [116]. With regard to ADRA2A gene, Perroud et al [117] showed an association between rs11195419 polymorphism and nortriptyline treatment-associated suicidal ideation in the GENDEP study.…”

“…Preliminary findings were provided for other BDNF SNPs (rs90887, rs61888800, rs7124442 and rs11030104) [179,182,183]. A strong association was established between rs962369 and an increase in suicidal ideation during antidepressant treatment [117]. Interestingly, some SNPs of the BDNF receptor gene NTRK2 were also associated with AD response [184] In addition, some variants within NTRK2 and also interactions between variants of BDNF and NTRK2 genes might have effect on antidepressant treatment-associated suicidality [117,185,186].…”