Impact of Inflammation on White Matter Integrity and Functional Connectivity in Chronic Major Depressive Disorder

Background: Inflammation is increasingly recognized as a pathophysiologic component of major depressive disorder (MDD). Concurrently, depressive episode chronicity has emerged as a significant predictor of adverse long-term outcomes. Methods: Utilizing data from the PReDICT (Predictors of Remission in Depression to Individual and Combined Treatments) study, our analysis included 201 participants who completed C-reactive protein (CRP) sampling and diffusion-weighted imaging scans; of these, 120 participants had usable functional magnetic resonance imaging scans. Chronicity was classified as the presence of a current depressive episode ≥2 years in duration. We examined the impact of inflammation on brain structure and function in MDD, focusing specifically on differences related to chronicity, as well as the interactions between inflammation and functional and structural alterations. Results: No significant correlations were observed between CRP concentrations and either functional connectivity (FC) or fractional anisotropy (FA). In patients with chronic, but not nonchronic, MDD, higher CRP concentrations were associated with lower FA in several neural pathways, including the cingulum and frontal aslant tracts. Significant CRP × MDD chronicity interactions were also observed for FC within the default mode network (DMN) and the salience network (SN). Moreover, mediation analyses demonstrated both direct and FA-mediated effects of CRP on FC within the SN in patients with chronic MDD. Conclusions: Interactions based on depressive episode chronicity between CRP and neurobiological function, potentially mediated by reductions in white matter integrity, suggest a potential pathophysiological process in some patients with chronic MDD. The differences in FC suggest specific compensatory adjustments within the DMN and SN among patients with chronic MDD.