Decoding Major Depressive Disorder: A Comprehensive Review of Neurobiological Pathways, Biomarker Signatures, and Therapeutic Advances

Abstract

Major depressive disorder (MDD) is a common and serious mental health disorder that arises from a complex combination of biological factors. Despite extensive scientific progress, the exact mechanisms responsible for its development are not entirely understood. Several interrelated processes—including imbalances in monoamine neurotransmitters, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, impaired neurogenesis and neuroplasticity, mitochondrial abnormalities, chronic neuroinflammation, and genetic as well as epigenetic influences—play important roles in the onset and continuation of depressive symptoms. Additionally, disturbances in glutamate and GABA signalling, alterations within the gut-brain axis, disruption of circadian rhythms, and defects in synaptic communication further contribute to the disorder’s complexity. Recognition of these mechanisms has guided the advancement of treatment strategies. While conventional therapies such as pharmacological antidepressants and psychotherapy continue to be widely used, innovative options—including ketamine-based treatments, neuromodulation techniques, anti-inflammatory agents, and therapies targeting the microbiome—are emerging as promising alternatives. This review summarizes the key biological pathways implicated in depression and examines both established and evolving therapeutic approaches designed to improve outcomes and support long-term patient recovery.