Major depressive disorder (MDD) affects over 280 million people worldwide and is associated with functional disability, reduced productivity, and impaired quality of life. Despite extensive research, its etiology and management remain complex and multi-factorial. This review critically examines contemporary etiological hypotheses, emerging biomarkers, and recent therapeutic advancements in MDD. A systematic search of PubMed, Embase, Scopus, and PsycINFO databases identified English-language studies relevant to pathophysiology and treatment. Stress-related mechanisms, including hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, elevated cortisol, and dysregulated inflammatory cytokines (e.g., IL-6, TNF-α), are consistently implicated. Neuroimaging and proteomic studies reveal structural and functional alterations in the prefrontal cortex, hippocampus, and amygdala, while genetic polymorphisms (e.g., BDNF Val66Met) are associated with susceptibility. Therapeutically, rapid-acting antidepressants such as ketamine achieve 50-70% response rates within 24 hours, compared with 30-40% for conventional SSRIs over 4-6 weeks. Non-pharmacological approaches, including cognitive-behavioral therapy and mindfulness-based interventions, show remission rates of 30-50% in moderate-to-severe depression. The integration of biomarker research with innovative treatments highlights the potential for personalized, patient-centered care. Future studies should focus on large-scale biomarker validation and the development of tailored therapeutic algorithms to optimize outcomes in MDD.
Thulasingam et al. (Thu,) studied this question.
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