Insulin Resistance as a Mediator of Suicide Risk in Bipolar Disorder: A Neurobiological and Imaging Study

BACKGROUND: Major depressive disorder (MDD) and bipolar disorder (BD) are associated with increased suicide risk and commonly feature metabolic dysfunctions such as insulin resistance (IR) and obesity. These conditions are also linked to systemic inflammation and white matter (WM) alterations, which may underlie suicidal behaviors. This study explores how immune-metabolic markers affect WM integrity and suicidality in mood disorders. METHODS: Inpatients with BD (n = 93) and MDD (n = 88) underwent diffusion tensor imaging to assess WM integrity. Blood samples were analyzed for insulin, glucose, and inflammatory markers. IR was assessed via HOMA-IR and QUICKI. Suicide risk was measured using the Beck Scale for Suicide Ideation (BSI) and the Hamilton Depression Rating Scale (HDRS). RESULTS: BD patients showed higher IR, BMI, and inflammation compared to MDD patients. In BD, both insulin and HOMA-IR positively correlated with suicide risk and were associated with increased suicidal ideation. BMI indirectly predicted suicide risk through IR, but not via inflammation. WM analysis revealed that in high-suicide-risk BD patients, higher insulin and HOMA-IR were associated with reduced fractional anisotropy and increased mean and radial diffusivity-markers of axonal and myelin disruption. These effects were not observed in MDD or BD patients with lower suicide risk. CONCLUSION: Insulin resistance emerges as a key contributor to suicidality in BD, possibly via its impact on WM integrity. Although BMI did not directly predict suicide risk, its effect through IR suggests metabolic health may be a modifiable target. Early intervention on IR and inflammation could benefit high-risk BD individuals.