Interleukins in Major Depressive Disorder: Lessons From Autoimmune Diseases and Pathways to Clinical Translation

Some MDD patients exhibit chronic, low-grade inflammation both systemically (in blood) and centrally (in CSF and brain). They show elevated pro-inflammatory IL-6, IL-1β, and IL-18, with insufficient anti-inflammatory IL-10. This immune dysregulation affects key neurobiological processes (monoamine metabolism, HPA axis, neurogenesis), linking inflammation to depressive symptoms. MDD and autoimmune diseases share inflammatory mediators and signaling pathways, supporting these as therapeutic targets; however, MDD's inflammation is low-grade and innate driven, whereas autoimmune diseases have high-grade, adaptive immune responses to specific antigens. Successful anti-IL therapies in autoimmune conditions provide a roadmap for treating inflammation-driven depression. Translating these findings to practice requires a precision immune-psychiatry approach. Biomarkers like C-reactive protein and IL-6 can identify an inflammatory depression subtype, and patients may benefit from targeted immunomodulatory strategies, repurposed biologics, novel small molecules, or lifestyle interventions particularly if standard antidepressants fail.