Neurobiological mechanisms and brain network dysfunction in major depressive disorder: an integrative review

Abstract

Major depressive disorder (MDD) is a prevalent and disabling psychiatric disorder characterized by persistent mood disturbances, cognitive impairments, and significant systemic consequences. Despite its substantial clinical burden, diagnosis remains challenging because current approaches rely largely on subjective symptom-based assessments and are complicated by marked biological and clinical heterogeneity. In this review, we synthesize findings from neuroimaging, electrophysiology, genetics, and molecular studies to provide an integrated overview of the structural, functional, and neurobiological alterations that underlie MDD. We discuss abnormalities involving large-scale brain networks, neuroplasticity and stress-related pathways, neuroinflammation, oxidative stress, and neurotransmitter systems, together with their implications for biomarker discovery, patient stratification, and treatment response. Collectively, current evidence implicates both molecular dysregulation and large-scale neural network dysfunction in MDD, although direct evidence linking alterations across these biological levels remains limited. Integrating multimodal biological and neuroimaging approaches may improve diagnostic precision, facilitate personalized therapeutic strategies, and advance the development of biologically informed psychiatry.