{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:24:10Z","timestamp":1793211850156,"version":"4.5.0"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.23033.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000}},{"DOI":"10.12688\/wellcomeopenres.23033.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000}},{"DOI":"10.12688\/wellcomeopenres.23033.3","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000}}],"reference-count":51,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["Cipriani"],"award-info":[{"award-number":["Cipriani"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["A."],"award-info":[{"award-number":["A."]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>Background Exercise for post-traumatic stress disorder (PTSD) is a potentially effective adjunct to psychotherapy. However, the biopsychosocial mechanisms of exercise are not well understood. This co-produced living systematic review synthesizes evidence from human and non-human studies. Methods We Included controlled human and non-human studies involving searches of multiple electronic databases (until 31.10.23). Records were screened, extracted, assessed for risk of bias, and reconciled by two independent reviewers. The primary outcome for human studies was PTSD symptom severity, while outcomes of interest for non-human studies included freezing behaviour, fear memory, fear generalization, startle response, and locomotion. Data were synthesised with random-effects meta-analysis. Results Eleven human studies and 14 non-human studies met the eligibility criteria. Results of human studies showed that exercise was not associated with symptom severity improvement compared to control (standardized mean difference [SMD] -0.08, 95% confidence interval [CI] -0.24 to 0.07). High-intensity exercise reduced PTSD symptoms scores more than moderate-intensity exercise. There was insufficient data to examine the effects of exercise on functional impairment, PTSD symptom clusters, and PTSD remission. Only three studies, all at high risk of bias, examined mechanisms of exercise with inconclusive results. Results of non-human studies showed that exercise was associated with improvement in all behavioural outcomes, including locomotor activity (SMD 1.30, 95% CI 0.74 to 1.87, 14 studies), and changes in several neurobiological markers, including increase in brain-derived neurotrophic factor (SMD 1.79, 95% CI 0.56 to 3.01). Conclusions While non-human studies provide compelling evidence for the beneficial effects of exercise, human trials do not. Evidence from non-human studies suggest that exercise might increase the levels of brain-derived neurotrophic factor, enhance cognitive appraisal, and improve perceived exertion. Overall, the paucity of data on the effectiveness of exercise in PTSD and mechanisms of action underscore the need for rigorous trials. Registration The protocol was registered with PROSPERO (ID:453615; 22.08.2023).<\/ns3:p>","DOI":"10.12688\/wellcomeopenres.23033.4","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T08:10:08Z","timestamp":1748333408000},"page":"720","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The therapeutic potential of exercise in post-traumatic stress disorder and its underlying mechanisms: A living systematic review of human and non-human 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network.","volume":"277","author":"P Szeszko","year":"2019","journal-title":"Psychiatry Res."},{"key":"ref-53","article-title":"The therapeutic potential of exercise in Post-Traumatic Stress Disorder and its underlying mechanisms: a living systematic review of human and non-human studies.","author":"S Wright","year":"2024"}],"container-title":["Wellcome Open 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.26150.r118167, Ryan S Garten, Virginia Commonwealth University, Richmond, Virginia, 06 Feb 2025, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-720\/v2#referee-response-118167","order":0,"name":"referee-response-118167","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.25365.r114973, Dharani Keyan, School of Psychology, University of New South Wales, Sydney, 30 Jan 2025, version 1, 2 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-720\/v1#referee-response-114973","order":1,"name":"referee-response-114973","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Simonne Wright87<\/b>; \n<i>Posted: 11 Mar 2025<\/i>; \n<u><b>Author response:<\/b><\/u>  We thank the reviewer for the recommendation to expand our discussion of biological and psychosocial mechanisms and alternative hypotheses related to the role of exercise in PTSD symptom modulation. However, on submission, we were required to limit the literature review to under 500 words and reduce the Discussion from 2,155 to 1,239 words. Given the word limit constraints, we prioritized key findings. We recognize the need to further engage with alternative mechanisms (e.g., distraction vs. potential exacerbation of intrusive memories).  We have taken note of the reviewer\u2019s request to expand the introduction and discussion. In order to meet journal requirements, we have added the additional text to the OSF folder, given that we cannot extend these sections in the manuscript itself (https:\/\/osf.io\/cxyjw). This has been indicated in the manuscript, at the end of the introduction section: \u201c\n<u>Please refer to the <\/u>Extended data\n<u> for the Expanded introduction and discussion section<\/u>.\u201d (pg 7).  Regarding the exclusion of human analogue studies (e.g., trauma film, fear conditioning, extinction paradigms) and the limitation to Single Prolonged Stress (SPS) models in non-human studies, we explicitly pre-specified our selection criteria. Specifically, we limited eligibility to controlled human and non-human studies. Further, we restricted non-human studies to SPS models as it is the most widely used paradigms in non-human studies of PTSD. Moreover, studies have shown that the SPS model in animals and human PTSD involve experiencing traumatic events that can lead to similar behavioural and physiological changes. Since our last literature search, we have conducted five updates, with no new eligible studies identified. We have provided details for updating the systematic review and stopping the living mode of the review in the protocol (https:\/\/wellcomeopenresearch.org\/articles\/8-494\/v2).  \u201cThe literature search will be updated every three months, and any new studies meeting the inclusion criteria will be incorporated into the latest version of the evidence. If sufficient new data exists, a triangulation meeting will be held to incorporate the new evidence. Furthermore, it will be decided whether the review updates will continue, and whether to widen the scope of the review (this may include contacting authors of major studies to provide missing data). When there is insufficient new data to warrant triangulation, the review will be updated again after three months\u201d. We appreciate the suggestion to make our included study list for human studies more accessible. We have now added a complete reference list of included studies in the Extended Data (https:\/\/osf.io\/qdmxz): \u201c\n<u>Please refer to the <\/u>Extended data\n<u> for the list of eligible human studies.\u201d<\/u> (pg 11) It is important to note in our inclusion criteria: \u201cWe excluded exercise interventions that incorporated mindfulness (e.g., Pilates, martial arts, yoga, tai chi, and horseback riding) or psychotherapy-based techniques into the exercise protocol.\u201d (pg 8) &nbsp; &nbsp;","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-720\/v4#referee-comment-6070","order":2,"name":"referee-comment-6070","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.26150.r115723, Jony Sheynin, Texas A&M University, Houston, Texas, 31 Mar 2025, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-720\/v2#referee-response-115723","order":3,"name":"referee-response-115723","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Simonne Wright87<\/b>; \n<i>Posted: 14 May 2025<\/i>; I appreciate the invitation to review this interesting manuscript. Indeed, it is important to understand the evidence from human and non-human literature on the therapeutic potential and the underlying mechanism of exercise in PTSD. Such knowledge would have a direct relevance to treatment of PTSD, and could also have implications for other mental conditions. Below I list some suggestions that authors might want to consider to further improve the manuscript: \n<u>Author response<\/u> Thank you for your kind and constructive feedback. We\u2019re glad that you found the topic and scope of our review to be relevant and of interest. We appreciate your thoughtful suggestions, which have helped us improve the clarity and rigour of the manuscript. Please find our detailed responses to each of your comments below:  Abstract: \u201cResults\u201d: Include results from \u201cnon-human studies\u201d, as well.   \n<u>Author response<\/u> Thank you, we've revised the abstract to clarify the non-human findings. &nbsp;  As the concept of a \u201cliving review\u201d is relatively novel, it would be helpful to define it at the beginning of the manuscript.  \n<u>Author response<\/u> We thank the reviewer for this helpful suggestion. In response, we have now added a clear definition of a living systematic review at the start of the Methods section to orient readers who may be unfamiliar with the concept. The revised text reads: \u201cA living systematic review is a form of evidence synthesis that is regularly updated to incorporate newly published studies, maintaining a current and dynamic understanding of the research landscape. This approach is especially useful in rapidly advancing areas of inquiry, where incorporating the latest findings in real time can meaningfully shape clinical decision-making and inform policy development (Elliott et al., 2014).\u201d (pg 8) &nbsp;  Methods; \u201cEligibility criteria\u201d - \u201cparticipants with either above-threshold symptoms on any standardized self-report measure or a clinical diagnosis of PTSD.\u201d: \u201cFuture recommendations\u201d could include studying participants with sub-threshold PTSD symptoms, i.e., individuals who develop some symptoms but are not diagnosed with PTSD, per se. Along the same line, there is evidence that trauma alone could cause alterations in neural signal (Lokshina et al 2021, Current Research in Psychiatry); Could exercise have positive effect then, as well?  \n<u>Author response<\/u> We thank the reviewer for raising this insightful point. However, we note that such investigations fall more squarely within the realm of prevention and early intervention prior to diagnosis of PTSD, rather than treatment per se, which is the primary focus of the current review. Given the broad scope of PTSD research, we believe it is important to maintain a clear focus to ensure conceptual clarity and methodological coherence in systematic reviews. &nbsp;  Methods; \u201cEligibility criteria\u201d: Please clarify why only the SPS animal model of PTSD has been included in the review of non-human studies (see Richter-Levin et al. 2019, PMID:&nbsp;30816289).  \n<u>Author response<\/u> Several different approaches to inducing a phenotype in animals which model features of PTSD have been employed.&nbsp; In addition to the critical review of Richter-Levin, a more recent systematic review (PMID:&nbsp;34054443) focussed on SPS as the most commonly used model. Zhang et al (PMID:&nbsp;31273708) and Deslauriers et al (PMID:&nbsp;29338843) together identify some 14 different approaches including some - such as Early Life Stress and Learned Helplessness - which may not selectively induce features of PTSD in distinction to other behavioural phonotypes. In this first iteration of this Living Systematic Review, and in the absence of strong empirical evidence to support the inclusion of other models, we elected to focus on SPS &nbsp;  Methods; \u201cOutcomes\u201d: \u201cFor human studies, the primary outcome was PTSD symptom severity....\u201d: please clarify that this refers to *total* symptoms, whereas the secondary outcomes refer to *symptom clusters*.  \n<u>Author response<\/u> We thank the reviewer for this useful suggestion. We have now clarified in the Methods section that the primary outcome, PTSD symptom severity, refers to the total PTSD symptom score: \u201cFor human studies, the primary outcome was \n<u>total<\/u> PTSD symptom severity. Secondary outcomes were functional impairment (e.g., disability, quality of life), avoidance symptom severity, reexperiencing symptom severity, hyperarousal symptom severity, negative cognitions and mood severity\u2026\u201d (pg 9) &nbsp;  Methods; \u201cStudy identification\u201d: It\u2019s not clear why search strategies for human and non-human studies used different databases; For instance, Why PubMed and preprints were used only for non-human studies?  \n<u>Author response<\/u> Thank you for this observation. The identification and screening of human and non-human studies were conducted independently, in line with the distinct methodological requirements and disciplinary publishing norms for each evidence stream. Human PTSD intervention studies are typically published in clinical, psychiatric, and psychological journals. Accordingly, our search for human studies prioritised databases such as MEDLINE, PsycINFO, CINAHL, and CENTRAL, which offer optimal coverage of clinical trials and health-related literature. Conversely, non-human studies, particularly those involving rodent models, are more commonly published in neuroscience, behavioural science, and preclinical research outlets, which are often indexed in PubMed and Web of Science, and increasingly appear as preprints in repositories like bioRxiv and medRxiv. &nbsp;  It would be helpful to clarify in the main text (i.e., not only Table 1) what are the comparison groups\/sham interventions that have been reported in the studies.  \n<u>Author response<\/u> Due to the manuscript word restrictions, we chose to add the comparison group types to Table 1. &nbsp;  Results; \u201cPTSD symptom severity\u201d: \u201cWe found that studies with exercise alone as intervention were associated with larger effects than those in studies where patients were additionally given treatment-as-usual or psychotherapy.\u201d: This is misleading. Please first clarify that there were no significant differences. Also, edit \u201ceffects\u201d to \u201ceffect sizes\u201d. Lastly, this finding is somewhat counter-intuitive; Why do authors think that the additional \u201ctreatment-as-usual\u201d might reduce the positive effect of exercise? &nbsp;\n<u>Author response<\/u>  To clarify, we report the results from a frequentist meta-analysis and do not make dichotomous claims about statistical significance. &nbsp;  There is growing literature on the neural biomarkers involved in PTSD treatment, as detected by functional MRI (e.g., see Rauch et al. 2018, PMID:&nbsp;29081351). However, in the current manuscript the research on neuroimaging\/fMRI is not discussed. I suggest to elaborate on this topic, and possibly propose studying this in the \u201cFuture recommendations\u201d section. &nbsp;\n<u>Author response<\/u>  We agree that there is a growing body of literature suggesting that symptom improvement in PTSD is associated with alterations in brain function, as detected by functional MRI. While we have not amended the manuscript to include this suggestion, as it extends beyond the current evidence base, we fully support this direction for future research. We have updated the discussion to include: \u201c\n<u>Furthermore, future research could benefit from the inclusion of neuroimaging techniques, such as functional MRI (fMRI), to explore how exercise modulates brain networks involved in PTSD. Evidence increasingly indicates that clinical improvement in PTSD is linked to functional changes in key neural regions (Szeszko &amp; Yehuda, 2019). Employing fMRI in exercise-based trials could provide insight into underlying mechanisms and help identify neural markers of PTSD treatment response<\/u>.\u201d (pg 21) &nbsp;  The manuscript mentions the positive effect of BDNF and AEA on fear extinction in PTSD; It would be helpful to first, mention the evidence on altered fear extinction in PTSD (see Lokshina et al. 2023, PMID:&nbsp;37535308). \n<u>Author response<\/u>  Thank you for this important suggestion. We agree that disrupted fear extinction is a core feature of PTSD and a key target for therapeutic mechanisms. Our Expanded Introduction and Discussion in the Extended data already includes a summary of the literature on impaired extinction learning in PTSD and highlights the role of BDNF and AEA in modulating these processes. Given the word constraints of the main manuscript, this broader context was placed in the extended data to maintain focus on findings from the included studies. &nbsp;  Authors mention that exercise-induced increase in BDNF may increase cognitive and emotional resilience in PTSD patients; Do authors think that indeed exercise could help with developing resilience to the development of PTSD? Could this be investigated in future work in individual before the occurrence of a traumatic event (e.g., in pre-deployment soldiers).  \n<u>Author response<\/u> We thank the reviewer for this insightful suggestion. As noted in our response to Comment 3, our review focused on exercise as a treatment for individuals with clinically significant PTSD symptoms, rather than on prevention or early interventions prior to the diagnosis of PTSD. However, we agree that the potential for exercise to build resilience prior to trauma exposure is a compelling research direction, particularly in high-risk populations such as military personnel or first responders. While beyond the current scope, we agree this is a promising area for future mechanistic and preventative research. &nbsp;","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-720\/v4#referee-comment-6125","order":4,"name":"referee-comment-6125","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"We are funded by Wellcome, a global charitable foundation. The funders had no role in the study design, data collection and analysis, or the preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":5,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}