Major depressive disorder (MDD) is one of the leading psychiatric causes of disability worldwide and is characterized by marked heterogeneity, high recurrence risk, and low treatment rates. Traditional models have emphasized monoaminergic neurotransmitter imbalance, hypothalamic-pituitary-adrenal axis dysfunction, structural and functional brain remodeling, and inflammatory activation. Although these perspectives have substantially advanced our understanding of MDD, they do not fully account for its complex pathogenesis, and further investigation may support the development of novel prevention and treatment strategies. Increasing evidence indicates that MDD is closely associated with endocrine and metabolic abnormalities. This review summarizes evidence suggesting that endocrine and metabolic dysregulation may provide mechanistic insights into symptom burden, variability in disease progression, and treatment difficulties in certain patients. Particular attention is given to five interrelated domains: shared genetic and environmental susceptibility, dysfunction of the hypothalamic-pituitary-target gland axes, chronic low-grade inflammation and immune imbalance, impaired insulin signaling, and disruption of cerebral energy metabolic homeostasis. The review further explores potential clinical implications, including targeted endocrine and metabolic assessment, metabolism-related pharmacological strategies, modulation of the gut-brain axis, and lifestyle interventions. Rather than simply describing associative findings, this review aims to identify endocrine and metabolic abnormalities with potential predictive, modifiable, and clinically meaningful value, thereby providing a cautious and evidence-based framework for future risk assessment, disease-course interpretation, and adjunctive treatment of depression.
