Abstract
Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition with limited treatment options for patients who are resistant to conventional pharmacological and psychotherapeutic interventions. Stem cell (SC)-based therapies have emerged as a promising experimental approach, offering multifaceted mechanisms of action including neurogenesis, immunomodulation, antioxidative protection, and neuromodulation. This narrative review synthesizes current evidence from preclinical studies and early-phase clinical trials on the efficacy of mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) in alleviating depressive-like behaviors. Mechanistic insights include enhanced hippocampal neurogenesis, modulation of the brain-derived neurotrophic factor (BDNF)-TrkB pathway, attenuation of neuroinflammation through microglial polarization, and restoration of serotonergic signaling via peripheral-to-central pathways such as via the vagus nerve. In addition, the therapeutic potential of extracellular vesicles (EVs) and intranasal administration as non-invasive delivery strategies is discussed. While animal and first preclinical studies suggest potential benefit, significant translational barriers remain, including issues of scalability, long-term safety, and ethical considerations. Further rigorous studies are needed to validate stem-cell-based therapies as viable treatments for MDD.