Complement-mediated synaptic loss in inflammatory depression: mechanisms and therapeutic prospects

Depression is a highly heterogeneous disorder involving diverse biological systems and pathogenic pathways. Clinical and prospective studies have revealed that a substantial proportion of patients present with elevated peripheral and central inflammatory cytokines, a phenotype strongly associated with poor response to standard antidepressants. The complement system has emerged as a pivotal upstream mediator that drives pathological neuroinflammation in depressive disorders. Overactivation of complement signaling drives glial activation, aberrant synaptic elimination, blood-brain barrier disruption, and neural circuit dysfunction. This process involves synergistic interactions between the C1q-C3-CR3 signaling axis and key regulatory proteins, including the high-mobility group box 1 protein, triggering receptor expressed on myeloid cells 2, Galectin-3, and neuronal pentraxin 2. Interventions targeting the complement system and its interacting proteins offer novel avenues for the treatment of inflammatory depression. The review systematically summarizes recent advances in the pathophysiological mechanisms of inflammatory depression and highlights the potential of complement-directed therapeutic strategies, aiming to provide actionable targets and fresh insights for drug development against this condition.