Disentangling the biological mechanisms underlying the effects of physical exercise in major depressive disorder: a comprehensive systematic review of randomized controlled trials.

BACKGROUND

Major depressive disorder (MDD) is a disabling psychiatric condition in which physical activity provides clinical benefits. While exercise effectively alleviates depressive symptoms, its biological mechanisms remain unclear.

METHODS

This systematic review investigated the neurobiological effects of physical exercise on biomarkers in adults with MDD through randomized controlled trials, including studies assessing exercise interventions and reporting data on their biological effects.

RESULTS

A total of 30 studies, including 2194 participants, were included, examining the effects of physical exercise on various biological systems in patients with MDD. Exercise interventions had mixed effects on inflammatory markers, including interleukins, C-reactive protein, and tumor necrosis factor-α, suggesting a potential but inconsistent anti-inflammatory role. Neurotrophic factors, such as brain-derived neurotrophic factor showed promise as biomarkers of treatment response, but their role in clinical improvements remained inconclusive. Findings for the stress-response system, including cortisol and monoaminergic systems, primarily involving serotonin and dopamine, were limited and variable. Exercise demonstrated potential benefits in reducing oxidative stress and enhancing β-endorphin levels, although these effects were not consistently observed.

CONCLUSION

This systematic review adopted a broader perspective than prior studies, exploring less-studied biological systems and identifying several limitations in the included studies, including small sample sizes, varying methodologies, and a predominant focus on biochemical markers. Future research should prioritize larger, standardized trials and particularly employ omics approaches to better understand the biological mechanisms underlying the effects of exercise in MDD. The findings highlight the complexity of exercise's biological effects and emphasize the need for further research to clarify its mechanisms.