Association of disease course and brain structural alterations in major depressive disorder.

INTRODUCTION: The investigation of disease course-associated brain structural alterations in Major Depressive Disorder (MDD) have resulted in heterogeneous findings, possibly due to low reliability of single clinical variables used for defining disease course. The present study employed a principal component analysis (PCA) on multiple clinical variables to investigate effects of cumulative lifetime illness burden on brain structure in a large and heterogeneous sample of MDD patients. METHODS: Gray matter volumes (GMV) was estimated in n = 681 MDD patients (mean age: 35.87 years; SD = 12.89; 66.6% female) using voxel-based-morphometry. Five clinical variables were included in a PCA to obtain components reflecting disease course to associate resulting components with GMVs. RESULTS: The PCA yielded two main components: Hospitalization reflected by patients' frequency and duration of inpatient treatment and Duration of Illness reflected by the frequency and duration of depressive episodes. Hospitalization revealed negative associations with bilateral dorsolateral prefrontal cortex (DLPFC) and left insula volumes. Duration of Illness showed significant negative associations with left hippocampus and right DLPFC volumes. Results in the DLPFC and hippocampus remained significant after additional control for depressive symptom severity, psychopharmacotherapy, psychiatric comorbidities, and remission status. CONCLUSION: This study shows that a more severe and chronic lifetime disease course in MDD is associated with reduced volume in brain regions relevant for executive and cognitive functions and emotion regulation in a large sample of patients representing the broad heterogeneity of MDD disease course. These findings were only partly influenced by other clinical characteristics (e.g., remission status, psychopharmacological treatment).

Mediation of the Association Between Vascular Risk Factors and Depressive Symptoms by C-Reactive Protein.

Background: This study examined whether C-reactive protein (CRP), a marker of low-grade systemic inflammation, mediates the association between vascular risk factor (VRF) burden and depressive symptoms. Methods: We drew on the prospective design of the UK Biobank to include participants with longitudinal data on VRF burden, CRP, and depressive symptoms. Total, direct, and indirect effects were estimated using regression-based mediation models while controlling for confounding by sociodemographic factors, baseline CRP, and baseline depression. Sensitivity analyses probed the robustness of results to unmeasured confounding. Results: We analyzed data from 10,470 participants from the UK Biobank (mean age = 56.75 years at baseline). Net of covariates, VRFs at baseline were associated with higher depressive symptoms at follow-up (total effect = 0.099; 95% CI, 0.002-0.163). CRP mediated this association (indirect effect = 0.010; 95% CI, 0.004-0.017), accounting for 10.0% (95% CI, 0.3%-30.0%) of the total effect of VRF burden on depressive symptoms. Exploratory analyses suggested that the total and indirect effects pertained to somatic depressive symptoms (tiredness and appetite). Conclusions: These results suggest that inflammation-promoting effects of VRFs may contribute to depressive symptoms in mid- and later life. However, the mediating pathway via CRP explains only a small part of the association between VRFs and depression after accounting for important covariates and may pertain to specific depressive symptoms. Future studies leveraging similar longitudinal designs are needed to further disentangle the time-varying effects between VRFs, inflammation, and certain depressive symptoms while addressing important confounders.