Volume 29, Issue 162, August 2025

The Synergy of physical activity and vitamin D₃ supplementation as a potential strategy to support depression treatment: biological mechanisms and intervention perspectives

Sebastian Polok^1♦, Małgorzata Wasilewska², Krzysztof Pietrzak², Adriana Potoczek³

¹University Clinical Hospital No. 1, Unii Lubelskiej 1, 71-252 Szczecin, Poland
²Karol Marcinkowski University Hospital, Zyty 26, 65-046 Zielona Góra, Poland
³University Clinical Hospital, Medyków 14, 40-752 Katowice, Poland

^♦Corresponding author
Sebastian Polok, University Clinical Hospital No. 1, Unii Lubelskiej 1, 71-252 Szczecin, Poland

ABSTRACT

Depression affects over 20 million people globally, causing disability and socioeconomic burdens. First-line treatments fail in 30-50% of patients. Novel approaches targeting neuroinflammation and synaptic deficits are needed. Physical activity and vitamin D₃ show promise for treatment-resistant depression. Evaluate effectiveness of vitamin D₃ & mechanisms, and combined physical activity & vitamin D₃ supplementation on depression symptom management. Conducted structured systematic PubMed/Google Scholar search (from 2015) for RCT, full research observational studies, and meta-analyses, with keywords (depression, physical activity, vitamin D₃, neuroinflammation, combined-interventions and mental health). Included English peer-reviewed human studies. Physical training reduced symptoms by 20-30%. This has been accounted for through upregulation of BDNF, normalization of HPA, and reduced inflammation. Vitamin D₃ supplementation (≥2800 IU/day) in vitamin D deficient groups (<50 nmol/L) was associated with an improvement in mood. This has been accounted for through enhanced production of serotonin and suppressed neuroinflammation. Combined interventions had greater symptom reduction then the monotherapy's, such as physical activity and Vitamin D₃, from combinations in treatment-resistant cases. Combined physical activity and Vitamin D₃ may provide an optimal combined treatment strategy for depression. Treatment must be personalized depending upon deficiency, status and severity. Research moving forward must focus on research of large-scale randomized controlled trials (RCTs) to provide solid evidence, followed by public health integrated interventions to transmit and work with knowledge findings on the implementation of findings.

Keywords: Depression, Physical activity, Vitamin D3, Neuroinflammation, Combined interventions, Mental health

Medical Science, 2025, 29, e128ms3634

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DOI: https://doi.org/10.54905/disssi.v29i162.e128ms3634

Published: 09 August 2025