Differentiating suicide risk in treatment-resistant depression: clinical and functional imaging correlates of suicidal ideation and attempt

• Functional neuroimaging distinguishes suicidal ideation from attempts in depression • Functional connectivity broadly higher in suicide ideator compared to attempt group. • Amygdala-parahippocampal connection positively linked to suicidal ideation severity. • Amygdala-parahippocampal connectivity inversely linked to anxiety and sexual abuse. • Connectivity-clinical symptom link seen only in those with suicide attempt history. Treatment-resistant depression (TRD) is associated with elevated suicide risk. While many individuals with TRD experience suicidal ideation (SI), only a subset progress to suicide attempts (SA). This study identifies resting-state functional connectivity (FC) differences between individuals with TRD who experience SI only and those with SA history, and examines how these neural differences relate to clinical and trait-level suicide risk factors. Resting-state functional MRI data were acquired from 41 individuals with TRD and lifetime SI, including 21 with no SA history (SI group) and 20 with a lifetime SA (SA group), alongside 47 age- and sex-matched healthy controls. FC was measured using the CONN FC toolbox. Associations between clinical features and connectivity markers explored the clinical relevance of neural differences. Group-level network-based statistics analyses identified FC differences among 11 ROIs and 9 connections (p-FDR < 0.05). The SA group exhibited lower FC than the SI group between the right anterior insula and bilateral anterior parahippocampal gyri (right: pFDR = 0.02; left: pFDR = 0.04), the left anterior middle temporal gyrus (pFDR = 0.04), and between the right anterior parahippocampal gyrus and the left amygdala (pFDR = 0.01). Within the SA group, SI severity (p = 0.005), anxiety severity (p < 0.001), and childhood sexual abuse scores (p < 0.001) were independent predictors of FC between the left amygdala and right anterior parahippocampal gyrus. This study highlights distinct neural signatures associated with SI and SA in individuals with TRD in regions implicated in emotional memory and self-referential processing. These neural markers meaningfully relate to clinical features and may differentiate SI and SA in TRD, advancing our understanding of suicide risk.