Anjali Anand, Payal Mittal
Major Depressive Disorder (MDD) is one of the world's most disabling conditions. The traditional model focuses on monoaminergic imbalance, neurotrophic deficits, and hypothalamic- pituitary-adrenal (HPA) axis dysfunction. However, this model does not fully account for the complex symptoms and treatment resistance observed in MDD. Recent research highlights new biological mechanisms: glymphatic dysfunction, ferroptosis, and Extracellular vesicles (EVs) signaling. These findings mark a significant shift in understanding MDD pathophysiology. This study systematically reviewed literature from PubMed, Scopus, and Web of Science (2018-2025). It identified 71 eligible studies with preclinical and clinical findings. Evidence shows that impaired glymphatic clearance disrupts the exchange between cerebrospinal fluid and the brain's interstitial fluid. A loss of aquaporin-4 (AQP4) polarization drives this disruption. The result is neuroinflammation, oxidative stress, and disturbed sleep. Ferroptosis is a type of iron-dependent cell death marked by lipid peroxidation and glutathione depletion. It reduces neuronal viability and plasticity in brain regions involved in mood regulation. This aggravates MDD. Meanwhile, changes in EV microRNA, proteins, and lipids affect neuroinflammatory signaling and synaptic integrity. These changes act both as mediators and biomarkers of disease progression. The interaction between these pathways increases oxidative stress, neuroinflammation, and synaptic dysfunction. Together, they constitute an interconnected pathophysiological framework of MDD biology. Therapeutic options include promoting glymphatic flow through sleep regulation, using ferroptosis inhibitors and antioxidants, and developing EV-based diagnostics and therapies. These mechanisms suggest MDD pathophysiology involves impaired glymphatic clearance, oxidative imbalance, and disrupted intercellular communication. They offer potential targets for mechanism-based, personalized treatment strategies.