Inflammation is a leading biological risk factor contributing to unfavorable outcomes of major depressive disorder (MDD). Both inflammation and depression are associated with similar alterations in brain structure, indicating that brain structural alterations could serve as a mediating factor in the adverse influence of inflammation on clinical outcomes in MDD. Nonetheless, longitudinal research has yet to confirm this hypothesis. Therefore, this study aimed at elucidating the relationships between peripheral inflammatory cytokines, gray matter volume (GMV) alterations, and antidepressant response in MDD. We studied 104 MDD patients treated with selective serotonin reuptake inhibitors and 85 healthy controls (HCs). Antidepressant response was assessed after 8-week antidepressant treatment by changes in 17-item Hamilton Depression Rating Scale (HAMD-17) scores. The GMV alterations were investigated using a voxel-based morphometry analysis. Inflammatory cytokines were measured using flow cytometry. Partial correlations were used to explore the relationships between inflammatory cytokines, GMV alterations, and antidepressant response. Compared to HCs, MDD patients showed reduced GMVs primarily in the frontal-limbic area, right insula, and right superior temporal gyrus. Furthermore, the alterations in GMVs, particularly in the right middle frontal gyrus and the left anterior cingulate gyrus, were associated with ΔHAMD-17 and inflammatory cytokines. Additionally, GMV alterations in the right middle frontal gyrus mediated the negative relationship between interleukin -1β and ΔHAMD-17. This study contributes to understanding the effect of inflammation on the brain and their relationships with antidepressant response, offering a potential explanation for the connection between inflammatory status and treatment efficacy.
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