Insulin/IGF-1 signaling modulation in prefrontal cortex is linked to antisuicidal effects in MDD

Suicide is a major cause of death worldwide, yet pharmacological options for alleviating suicidality remain limited. Clozapine and ketamine are among the few small molecules with well-documented anti-suicidal effects, direct evidence linking their molecular activity to the genetics of suicide has been scarce. In this study, we conducted a transcriptome-wide association analysis of suicide phenotypes in the prefrontal cortex (Brodmann area 9) of 172 patients with major depressive disorder (MDD). This allowed us to define genetic signatures associated with suicidal behavior. We then inverted these signatures and, using SigCom LINCS L1000 consensus signatures, ranked small molecules by the similarity of their induced expression changes. Both ketamine and clozapine were significantly prioritized in this analysis. Further examination at the individual-gene level revealed that the prioritization of these two compounds was driven by the downregulation of insulin receptor substrate 2 ( IRS2 ), a key mediator of IGF-1 and insulin signaling. In line with this finding, compounds known to upregulate IRS2 - such as IGF-1 inhibitors, glucocorticoid agonists, and PI3K and MTOR inhibitors - showed negative enrichment in the prioritization. These observations suggest a common mechanistic link between the transcriptional responses to ketamine and clozapine and the genetic signatures associated with suicide in MDD.