Neuroinflammation and Stress-Driven Mechanisms Underlying Major Depressive Disorder: Emerging Insights and Therapeutic Targets

Major depressive disorder (MDD) is a highly prevalent and debilitating psychiatric illness characterized by persistent low mood, anhedonia, cognitive impairment, and diminished self-worth. Despite extensive investigation into its etiology and neurobiological underpinnings, current pharmacological and psychotherapeutic interventions exhibit limited efficacy and delayed onset of action in a substantial proportion of patients. Emerging evidence indicates that stress-induced neuroinflammatory processes play a critical role in the initiation and progression of depressive pathology. In particular, chronic stress triggers excessive activation and maladaptive crosstalk between microglia and astrocytes within the central nervous system, leading to sustained elevation of pro-inflammatory cytokines, chemokines, and oxidative mediators. These neuroimmune alterations disrupt synaptic plasticity, impair neurogenesis, and dysregulate monoaminergic and glutamatergic neurotransmission, thereby contributing to depressive-like behaviors. Novelty of this review comprehensively summarizes the molecular and cellular mechanisms through which neuroinflammation drives the pathophysiology of depression, with a specific focus on microglial–astrocytic interactions and inflammatory signaling cascades. Furthermore, it highlights the therapeutic potential of small-molecule compounds with anti-inflammatory and immunomodulatory properties as novel treatment strategies for MDD. Elucidating the precise stress-responsive neuroimmune mechanisms, particularly through advanced approaches such as single-cell RNA sequencing to define glial subpopulations and their dynamic interactions, is essential for the development of targeted, mechanism-based therapies for major depressive disorder.