Internalizing-externalizing traits as mediators from depression to suicidal acts: Triangulating clinical evidence,...

The exact psychopathological mechanisms are still poorly understood, despite depression being strongly linked to suicidal acts. Potential differential mediators of suicidal acts in emerging dimensional insights include the internalizing-externalizing spectrum, with neuroticism and impulsivity as core features. Notwithstanding these findings, inquiries persist concerning: (1) their causal specificity versus synergistic effects, (2) the underlying neurobiological implications, and (3) the potential for clinical translation. Our study addresses these gaps through an innovative multi-method framework integrating.

A best-evidence synthesis of 28 studies was performed to evaluate observational associations. Then we analyzed genome-wide association summary data (neuroticism N = 274,108; impulsivity N = 1534; depression N = 499,799; suicidal acts N = 218,792) via Mendelian Randomization (MR) to investigate whether genetically predicted personality mediated the depression to suicidal acts. The Allen Human Brain Atlas was employed to perform gene enrichment analysis.

The observational synthesis found strong evidence that neuroticism was linked to depression to suicidal acts, while impulsivity findings were inconclusive. MR also found that neuroticism significantly mediated the depression to suicidal acts relationship (OR = 1.162, 95 % CI = 1.095-1.233; p < 0.001), while impulsivity showed no causal effect (OR = 0.999, 95 % CI = 0.949-1.052; p = 0.975). Brain-specific gene enrichment analysis showed depression to suicidal acts was enriched in the substantia nigra (p = 0.038, corrected), implicating dopaminergic dysfunction.

This integrative study demonstrates that neuroticism, but not impulsivity, causally mediates suicidal acts in depression, with dopaminergic pathways as a plausible neural substrate. Through this research, we propose personality-specific interventions targeting internalizing traits and high-risk patients with nigro-related dysfunction.