Exercise as an Adjunctive Treatment Modality for Major Depressive Disorder: A Multi-Omics Perspective

Major Depressive Disorder (MDD) is characterized by genetic and environmental factors. Current interventions, including selective serotonin reuptake inhibitors and cognitive-behavioural therapy, are often effective yet prone to the development of treatment resistance. A major mechanism for MDD pathogenesis involves dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, which results in chronic elevation of cortisol. Cortisol has been linked to MDD symptomology through downstream cellular effects, which can be elucidated through multi-omics analyses such as genomics (NR3C1, FKBP5), proteomics (pro-inflammatory cytokines), and metabolomics (shifted kynurenine pathway). A systematic literature search of OVID Medline and similar databases was conducted over the past 10 years to identify studies investigating exercise interventions targeting multi-omics markers in MDD. Inclusion criteria required independent MDD cohorts and included a minimum of two omics levels, and their relationship to exercise as an intervention. Existing literature demonstrates that aerobic exercise can regulate cortisol levels, increasing NR3C1 and FKBP5 gene expression, while reducing proinflammatory cytokines, and shifting tryptophan metabolism towards the neuroprotective kynurenic acid and away from neurotoxic metabolites. A change in these biomarkers suggests that regular physical activity can exert widespread biological and neurological effects, regulating molecular dysfunctions at a multi-omic level in MDD. Exercise, when prescribed as an adjunct to conventional MDD therapies, may improve clinical outcomes by modulating stress-responsive and inflammatory pathways at multiple omics levels. Further large-scale and longer-term randomized trials are required to validate specific biomarkers for personalized medicine, and additional work should investigate sex-based differences in exercise efficacy. Exercise offers significant promise for optimizing MDD management and promotes greater physiological resistance to depressive symptoms.