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Cited by 176Treatment of Major DepressionPhysical Activity and HealthStress Responses and Cortisol

The role of exercise in the treatment of depression: biological underpinnings and clinical outcomes

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Ross, Ryan E., VanDerwerker, Catherine J., Saladin, Michael E., Gregory, Chris M.·2023·Molecular Psychiatry
DOI 10.1038/s41380-022-01819-wPMC PMC9969795
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Abstract

Globally, depression is a leading cause of disability and has remained so for decades. Antidepressant medications have suboptimal outcomes and are too frequently associated with side effects, highlighting the need for alternative treatment options. Although primarily known for its robust physical health benefits, exercise is increasingly recognized for its mental health and antidepressant benefits. Empirical evidence indicates that exercise is effective in treating individuals with depression; however, the mechanisms by which exercise exerts anti-depressant effects are not fully understood. Acute bouts of exercise have been shown to transiently modulate circulating levels of serotonin and norepinephrine, brain-derived neurotrophic factor, and a variety of immuno-inflammatory mechanisms in clinical cohorts with depression. However, exercise training has not been demonstrated to consistently modulate such mechanisms, and evidence linking these putative mechanisms and reductions in depression is lacking. The complexity of the biological underpinnings of depression coupled with the intricate molecular cascade induced by exercise are significant obstacles in the attempt to disentangle exercise's effects on depression. Notwithstanding our limited understanding of these effects, clinical evidence uniformly argues for the use of exercise to treat depression. Regrettably, exercise remains underutilized despite being an accessible, low-cost alternative/adjunctive intervention that can simultaneously reduce depression and improve overall health. To address the gaps in our understanding of the clinical and molecular effects of exercise on depression, we propose a model that leverages systems biology and multidisciplinary team science with a large-scale public health investment. Until the science matches the scale of complexity and burden posed by depression, our ability to advance knowledge and treatment will continue to be plagued by fragmented, irreproducible mechanistic findings and no guidelines for standards of care.

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  • Exercise activities may also not produce consistent outcomes as an antidepressant due to the complex nature of biological underpinnings of depression when paired with sophisticated molecular cascade induced by physical exercise.

    “Exercise activities may also not produce consistent outcomes as an antidepressant due to the complex nature of biological underpinnings of depression when paired with sophisticated molecular cascade induced by physical exercise. 68”

    From Mixed reality technology for older adults: Evaluating the impact of a novel virtual humanoid coach in a community-based physical exercise program in the Philippines (2024) · cites this paper as [68]

    The Abstract says the complexity of depression biology and exercise’s molecular effects makes it difficult to disentangle how exercise affects depression. It does not say that this complexity causes inconsistent antidepressant outcomes; instead, it says clinical evidence uniformly supports exercise as a treatment. The section on immuno-inflammation likewise distinguishes uncertain mechanisms from robust clinical effects. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Ross, R. E., VanDerwerker, C. J., Saladin, M. E., & Gregory, C. M.
Affiliations
Medical University of South Carolina (US)
Corresponding author
Ross, Ryan E.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-10-17
Volume
28
Issue
1
Pages
298-328
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-022-01819-w
PMC
PMC9969795
OpenAlex
W4306404560
Cited by
176
References
40
Citations by year
2026: 37 · 2025: 65 · 2024: 53 · 2023: 21
FWCI
4.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs (IK1 RX002962)
  • Craig H. Neilsen Foundation
  • U.S. Department of Health & Human Services | National Institutes of Health (R01HD095137)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Physiology › Physical Activity and Health
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
physical activity, depression, antidepressant effects of exercise, serotonin, norepinephrine, brain-derived neurotrophic factor, neuroinflammation, exercise training, adjunctive therapy, systems biology
MeSH terms
Antidepressive Agents, Depression, Humans, Mental Health, Exercise

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