White Matter Microstructure in Suicide and Treatment-Resistant Depression

Abstract

Background. Major depressive disorder (MDD) is a leading cause of death and disability worldwide, and many individuals with MDD will experience treatment-resistant depression (TRD). TRD can lead to the development of suicidal ideation and behaviours, and up to 30% of people with refractory depression will attempt suicide at some point in their life. A neurobiological understanding of suicide is lacking, and neuroimaging markers of illness may elucidate the relationship between suicidal ideation and attempt. Diffusion tensor imaging (DTI) is a particularly sensitive neuroimaging modality that quantifies the microstructural integrity of white matter tracts, which may be useful in the investigation of psychiatric disease. The source of white matter changes may be further elucidated using free water imaging to isolate signal specific to the fibre tract and quantify the fractional volume of the free water compartment. Methodology. For this study, data were obtained from N=36 outpatients with TRD (n=20 suicide ideators and n=16 suicide attempters). Clinical characteristics of the patient sample were examined using clinician-rated and self-report questionnaires of depression and suicidal ideation severity. Whole-brain analysis of DTI data was conducted using tract-based spatial statistics (TBSS) via FMRIB Software Library (FSL) to identify between-group differences in white matter microstructure between suicide ideators and attempters. Free water imaging correction was applied through estimation of a constrained bi-tensor model via an in house MatLab-based script developed at Harvard University. Between-group differences of suicide ideators versus attempters were identified at a family-wise error (FWE) corrected significance threshold of p≤0.05. Subsequent exploratory analyses were performed at an uncorrected significance threshold of p≤0.01. Results. Suicide attempters had greater family history of suicide attempt, higher self-reported suicidal ideation severity, and were more likely to have received overnight treatment in a psychiatric facility in the past. TBSS revealed elevated mean diffusivity (MD), axial diffusivity (AD) and free water (FW) in suicide attempters compared to suicide ideators (thresholded p=<0.05, family-wise error corrected). Subsequent exploratory analyses revealed reduced fractional anisotropy (FA) and elevated radial diffusivity (RD) in fronto-thalamo-limbic white matter tracts of suicide attempters (thresholded p=<0.01, uncorrected). Free water correction appeared to increase detection of fractional anisotropy changes and suppress spurious differences in axial and radial diffusivity. Conclusion. The identification of significantly altered diffusion metrics in suicide attempters compared to suicide ideators suggests white matter pathology in TRD and suicide attempt. The effect of free water correction on diffusion metrics and the elevation of free water itself provide evidence toward the source of anisotropic changes. Future investigations to explore the combined impact of these measures in suicide and depression are recommended.