Genome-Wide Association Study of Antidepressant Treatment-Emergent Suicidal Ideation

Abstract

Emergence of suicidal ideation (TESI) during treatment with antidepressants in major depression led to a black box warning. We performed a genome-wide association study to identify genetic markers, which increase the risk for this serious side effect. TESI was evaluated in depressed in-patients (N ¼ 397) and defined by an emergence of suicidal thoughts during hospitalization without suicidal thoughts at admission using the suicide item (3) of the Hamilton Depression Rating Scale. Genotype distribution of 405.383 singlenucleotide polymorphisms (SNPs) in patients with TESI (N ¼ 32/8.1%) was compared to patients without increase in suicidal ideation (N ¼ 329/82.9%) and to a subgroup never reported suicidal ideation (N ¼ 79/19.9%). Top results were analyzed in an independent sample (N ¼ 501). None variant reached genome-wide significance, the best associated SNP was rs1630535 (p-value ¼ 1.3 Â 10 À7 ). The top 79 SNPs could be analyzed in an independent sample, and 14 variants showed nominal significant association with the same risk allele in the replication sample. A discriminant analysis classifying patients using these 79 SNPs revealed a 91% probability to classify TESI vs non-TESI cases correctly in the replication sample. Although our data need to be interpreted carefully owing to the small numbers in both cohorts, they suggest that a combination of genetic markers might indeed be used to identify patients at risk for TESI.

The molecular bases of the suicidal brain

“…Genome-wide association studies (GWASs) of suicidal behaviour or of treatment-emergent suicidal events have more recently been carried out to identify novel loci (see Supplementary information S1 (table)) [29][30][31][32][33][34] . Although these have mostly produced inconclusive or inconsistent results, it is notable that such approaches facilitate an un biased analysis of molecular pathways that are implicated in disease and are an important method to use.…”

Genome-wide association studies of suicidal behaviors: A review

“…Finally, Menke et al (2012) also performed a GWAS on TESI, with ideation measured by item 3 on the Hamilton Depression Rating Scale, during the first 12-weeks following treatment with a variety of different SSRIs. No significant associations were observed in the discovery sample, whereby 79 suggestive SNP associations with lowest Pvalues were instead used for testing in an independent replication sample.…”

Ten years after the FDA black box warning for antidepressant drugs: a critical narrative review

“…The results suggest that combinations of some genetic markers could be used to identify patients with this risk 78 . Additionally, an investigation into clinical and genetic predictors of the increase of suicidal ideation by patients undergoing therapy with AD assessed the effects of paroxetine, venlafaxine, and clomipramine.…”