Natural synergistic interventions for depression: Voluntary wheel running and flavonoids.

The objective of this review is to systematically investigate the combined antidepressant effects of voluntary wheel running and flavonoid supplementation, with a focus on their application as a natural intervention strategy for depression. A comprehensive electronic search was conducted across PubMed, Web of Science, and Scopus, excluding physical materials, and was restricted to literature published in English. Through a multidimensional comparative analysis of forced exercise versus voluntary physical activity, synthetic drugs versus natural flavonoids, and single versus combined interventions, this review clarifies the unique advantages and antidepressant mechanisms of this combined strategy. We examine how these interventions, both independently and in combination, alleviate depressive-like behaviors and modulate associated neurochemical markers in animal models, and mitigate depressive symptoms in human participants. The findings demonstrate that both voluntary exercise and flavonoid intake independently alleviate depressive-like behaviors in animal models and depressive symptoms in human participants, with these effects mediated through mechanisms including neurotransmitter regulation, anti-inflammatory effects, and antioxidant pathways. Notably, the combined intervention shows a synergistic effect, providing more significant benefits for alleviating depressive-like symptoms in animals and reducing depressive symptoms in humans, preventing disease onset, and promoting overall mental well-being. These results suggest that integrating voluntary wheel running with flavonoid supplementation could represent a promising non-pharmacological approach to managing depression.