Physical activity as an adjunctive intervention in the treatment of depression: a review of neurobiological, immunological, and gut-brain axis mechanisms

Abstract

Background: Major depressive disorder (MDD) poses a significant global burden. Since a large proportion of patients do not achieve full remission with standard pharmacotherapy alone, there is a pressing need for pleiotropic adjunctive interventions. Aim: To synthesize current evidence on the pleiotropic neurobiological, immunological, and gut-brain axis mechanisms that drive the antidepressant effects of physical activity. Material and methods: A narrative review of the medical literature was conducted using PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar databases, covering the years 2003–2026. Ultimately, 33 research papers were included, with a particular focus on network meta-analyses and evidence-based medicine (EBM) clinical guidelines. Results: Structured physical exercise modulates the reactivity of the hypothalamic-pituitary-adrenal (HPA) axis to psychosocial stress and strongly stimulates neurogenesis in the atrophic hippocampus through the release of brain-derived neurotrophic factor (BDNF). Furthermore, recent studies highlight the critical role of contracting skeletal muscles as a detoxifying organ that converts neurotoxic kynurenine into kynurenic acid. Similarly, aerobic training strengthens the epithelial barrier and optimizes the gut microbiome, thereby suppressing systemic neuroinflammation. Conclusions: Physical activity appears to be a highly effective, multidirectional therapeutic intervention. Beyond alleviating core depressive symptoms with an efficacy comparable to standard psychopharmacotherapy, it is the only method that radically reduces premature cardiovascular mortality in this patient population.