Recent Understanding on Genetic and Neurobiological Alterations in Major Depressive Disorder

Major depressive disorder (MDD) is a leading cause of disability worldwide, characterized by persistent low mood, anhedonia and cognitive impairments. Despite advancements in understanding its multifactorial aetiology, treatment outcomes remain inconsistent due to the complex interplay of genetic and neurobiological factors. A systematic review was conducted following PRISMA guidelines using databases including PubMed, Scopus, Web of Science and PsycINFO. Studies from 2000 to 2025 were included if they covered genetic polymorphisms, neurobiological markers or molecular pathways in MDD. Analysis of 87 studies identified 13 key genes and 19 biological markers linked to MDD. Genetic polymorphisms like SLC6A4, TPH2, BDNF Val66Met and FKBP5 influence neurotransmitter synthesis, neuroplasticity and HPA axis regulation. Neurobiological markers including cortisol, BDNF, CRP, IL-6 and serotonin levels exhibit consistent dysregulation in MDD patients. Associations of genetic and biomarker alterations with MDD symptomatology and treatment outcomes are summarized. Through GeneMANIA, we constructed a functional gene interaction network of the selected 13 genes, which exhibits strong functional connectivity through physical interactions (66.18%), co-expression (20.86%) and co-localization (12.97%). In conclusion, MDD arises from multifactorial genetic and neurobiological alterations. The trend towards personalised medicine is supported by a number of genes and biomarkers that exhibit promise as diagnostic and prognostic tools. However, additional meta-analytic and longitudinal research is required to validate these relationships due to the variety in study designs and demographics.