Between biochemical pathways and physiological dysfunction in major depressive disorder: A systematic review.

Abstract

Objective: To explore the relationship between key biochemical pathways and their associated physiological dysfunctions in major depressive disorder. Study Design: Systematic Review. Setting: PubMed, Scopus, Web of Science, and Google Scholar. Period: 2000-2025. Methods: Comprehensive literature search was conducted using major databases, including PubMed, Scopus, Web of Science, and Google Scholar for studies published between 2000 and 2025. Studies were included if they involved human subjects diagnosed with MDD and examined biochemical pathways such as neurotransmitter systems, hypothalamic–pituitary–adrenal (HPA) axis dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and neuroplasticity in relation to physiological outcomes. A total of 62 studies met the inclusion criteria and were included in the qualitative synthesis. Results: The review revealed that multiple biochemical abnormalities are consistently associated with physiological dysfunction in MDD. Neurotransmitter imbalances, particularly involving serotonin and dopamine, were commonly reported. Dysregulation of the HPA axis with elevated cortisol levels was frequently observed. Increased inflammatory markers, including pro-inflammatory cytokines, were also widely documented. Additionally, oxidative stress and mitochondrial dysfunction were linked to impaired cellular function and reduced energy metabolism, while decreased levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) were associated with reduced neuroplasticity. These pathways were found to interact and contribute collectively to both central and systemic manifestations of the disorder. Conclusion: This systematic review concludes that major depressive disorder is associated with multiple interacting biochemical pathways, including neurotransmitter imbalance, HPA axis dysregulation, inflammation, and oxidative stress. These alterations are closely linked with physiological dysfunctions affecting both brain and systemic functions. Understanding these integrated mechanisms may help in developing targeted and personalized treatment strategies for MDD.