The complement system in the pathophysiology and treatment of depression: From synaptic pruning to pharmacological targeting.

Major depressive disorder remains unsatisfactorily addressed by monoaminergic antidepressants, and the search for mechanistically novel targets has converged on the immune system. Among these, the complement system offers a defined molecular route through which locally synthesized complement proteins may tag synapses for microglial engulfment. Preclinical studies implicate the C1q-C3-CR3 pruning axis and the anaphylatoxin receptors C3aR and C5aR in linking immune activation to region-dependent synaptic and neuroinflammatory changes, but causal evidence in patients remains absent. This review synthesizes genetic and pharmacological studies of C3, C3aR, and C1q in stress- and inflammation-based animal models; critically appraises the heterogeneous human biomarker and large-scale proteomic literature; and organizes candidate pharmacology into natural products and small molecules, established drugs with secondary complement-related actions, and clinical-stage complement inhibitors developed for other indications. We emphasize that no randomized controlled trial has tested deliberate complement inhibition in depression and that physiological complement functions, infectious risk, CNS delivery, regional heterogeneity, sex, and patient selection remain major barriers. Complement therefore represents a testable, biomarker-linked therapeutic hypothesis rather than an established treatment mechanism, requiring stratified trials with direct pharmacodynamic evidence.