Oxidative stress in major depressive disorder: from experimental models to clinical therapeutic perspectives

Major depressive disorder (MDD) is a highly prevalent psychiatric condition with complex and multifactorial pathophysiology. Increasing evidence suggests that oxidative stress, defined as an imbalance between reactive oxygen species (ROS) production and antioxidant defense systems, plays a central role in the onset and progression of MDD. This narrative review integrates findings from preclinical animal models, clinical studies and therapeutic interventions to provide a comprehensive overview of oxidative stress in MDD. Compared with healthy controls, patients with MDD consistently exhibit increased lipid peroxidation products, protein and DNA oxidation markers, and altered antioxidant defenses, including glutathione and superoxide dismutase. Animal models including chronic unpredictable mild stress, chronic social defeat stress, and lipopolysaccharide administration consistently demonstrate that oxidative stress drives depressive-like behaviors through mechanisms affecting dendritic spine density, glutamatergic function, and hippocampal neurogenesis. Additionally, oxidative stress is closely linked to inflammatory signaling and redox-regulatory signaling pathways, such as NF-κB and Nrf2/Keap1, highlighting its function as a major modulator of neuronal dysfunction in MDD. Therapeutic strategies targeting oxidative stress and spanning from conventional antidepressants to antioxidant compounds, stem cell therapies, natural products, and physical exercise demonstrate promising potential in restoring redox balance and improving depressive symptoms, although high heterogeneity across studies has been reported. Collectively, these findings support oxidative stress as a unifying mechanism in MDD pathophysiology and a promising target for novel diagnostic and therapeutic approaches.