Repurposing Selective Serotonin Reuptake Inhibitors as Immunomodulators: Effects on Macrophage Activation and Polarization.

Depression is increasingly recognized as a systemic disorder in which immune dysregulation and chronic low-grade inflammation contribute to disease pathophysiology. Selective serotonin reuptake inhibitors (SSRIs), the most widely prescribed antidepressants, therefore, occupy a unique position at the interface of neuropsychiatry and immunology. Beyond their established central nervous system effects, accumulating preclinical and translational evidence suggests that SSRIs can modulate innate immune responses, particularly through effects on macrophage activation, cytokine production, and intracellular inflammatory signaling pathways. This review synthesizes current mechanistic, translational, and disease-oriented studies examining the immunomodulatory actions of commonly used SSRIs, with a specific focus on macrophage biology. Across experimental systems, patient-derived immune cells, and disease contexts, SSRIs do not function as uniformly anti-inflammatory agents. Rather, their effects are highly context dependent, varying across individual drugs, macrophage activation states, cellular microenvironments, and pathological settings. Recurrent immunological themes identified across preclinical and translational studies include modulation of IL-6 associated inflammatory responses, regulation of Toll-like receptor dependent signaling, engagement of GPCR-linked pathways, and sigma-1 receptor-mediated control of cellular stress responses. By organizing a fragmented literature into a macrophage-centered framework, this review highlights how SSRIs may, in some contexts, influence inflammatory recalibration, supporting further investigation of their potential repurposing as adjunctive immunomodulatory agents.