{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T05:16:22Z","timestamp":1783314982965,"version":"3.54.6"},"update-to":[{"DOI":"10.12688\/f1000research.140970.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000}},{"DOI":"10.12688\/f1000research.140970.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000}},{"DOI":"10.12688\/f1000research.140970.3","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000}},{"DOI":"10.12688\/f1000research.140970.4","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000}},{"DOI":"10.12688\/f1000research.140970.5","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000}},{"DOI":"10.12688\/f1000research.140970.6","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000}},{"DOI":"10.12688\/f1000research.140970.7","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000}}],"reference-count":40,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PREDOCTORAL GRANT BY THE UNIVERSITY OF THE BASQUE COUNTRY","award":["UPV\/EHU"],"award-info":[{"award-number":["UPV\/EHU"]}]},{"name":"PREDOCTORAL GRANT BY THE UNIVERSITY OF THE BASQUE COUNTRY","award":["PIF19\/40"],"award-info":[{"award-number":["PIF19\/40"]}]},{"name":"Convocatoria de Ayudas de Investigaci\u00f3n e Innovaci\u00f3n de la Red de Salud Mental de Araba 2022"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns5:p>Background The objective of this systematic review was to analyze the effects of physical activity (PA) intervention as an adjuvant strategy to pharmacological treatment in people with treatment-resistant depression (TRD) and non-remitted depression (NRD). Methods A search strategy was conducted from five databases: PubMed, Cochrane Central Register of Controlled Trials, Scopus, SPORTDiscus, and Web of Science. The Physiotherapy Evidence Database and Oxford\u2019s Evidence Levels were used to classify the quality appraisal. Results Of the 10777 records, 11 randomized controlled studies met the inclusion criteria, comprising 567 participants (n=275 from the TREAD project across eight sub-studies; n=292 from three independent Randomized control trials). The main outcome for this analysis was the effect of physical activity (PA) or exercise on depressive symptoms in people with TRD and NRD diagnosis. According to the FITT (Frequency, Intensity, Time, and Type) principle, there was some variability in the PA intervention. However, except for one article, all were classified as excellent in terms of quality description. Conclusions Based on moderate-quality evidence from three independent RCTs, structured exercise programs may be considered as an adjunctive intervention for depressive symptoms in patients with TRD and NRD. Evidence for other outcomes (quality of life, sleep, cognition, biomarkers) is of low or very low quality, derived from single studies or non-independent TREAD sub-analyses. Future research should prioritize independent replication of secondary outcomes and pre-specified analyses of predictors of response. Further high-quality RCTs in this population are urgently needed to confirm these findings and establish optimal PA protocols.<\/ns5:p>","DOI":"10.12688\/f1000research.140970.8","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T10:49:24Z","timestamp":1782902964000},"page":"1517","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Physical activity in the treatment-resistant depression and non-remitted depression: a systematic review of randomized controlled trials"],"prefix":"10.12688","volume":"12","author":[{"given":"Jos\u00e9","family":"Etxaniz-Oses","sequence":"first","affiliation":[{"name":"FACULTY OF PHYSICAL EDUCATION AND SPORT VITORIA-GASTEIZ BASQUE COUNTRY 01007 UNIVERSITY OF THE BASQUE COUNTRY (UPV\/EHU)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagore","family":"Iriarte-Yoller","sequence":"additional","affiliation":[{"name":"Araba Mental Health Network VITORIA-GASTEIZ BASQUE COUNTRY 01006 Osakidetza Basque Health Service"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikel","family":"Tous-Espelosin","sequence":"additional","affiliation":[{"name":"FACULTY OF PHYSICAL EDUCATION AND SPORT VITORIA-GASTEIZ BASQUE COUNTRY 01007 UNIVERSITY OF THE BASQUE COUNTRY (UPV\/EHU)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2622-5385","authenticated-orcid":false,"given":"Sara","family":"Maldonado-Martin","sequence":"additional","affiliation":[{"name":"FACULTY OF PHYSICAL EDUCATION AND SPORT VITORIA-GASTEIZ BASQUE COUNTRY 01007 UNIVERSITY OF THE BASQUE COUNTRY (UPV\/EHU)"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"129-133","DOI":"10.1016\/s0004-9514(09)70043-1","article-title":"The PEDro scale is a valid measure of the methodological quality of clnical trials: a demographic study.","volume":"55","author":"N Morton","year":"2009","journal-title":"Aust. 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We will include your suggestions in the next version of the manuscript once the editor permits us.","URL":"https:\/\/f1000research.com\/articles\/12-1517\/v8#referee-comment-15250","order":1,"name":"referee-comment-15250","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.168194.r307276, Michele Schmitter, Depression Expertise Center, Pro Persona Mental Health Care, Nijmegen, 02 Aug 2024, version 2, 1 approved with reservations, 1 not approved","URL":"https:\/\/f1000research.com\/articles\/12-1517\/v2#referee-response-307276","order":2,"name":"referee-response-307276","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>SARA MALDONADO-MARTIN<\/b>; \n<i>Posted: 18 Aug 2024<\/i>; \n<b>ANSWER TO REVIEWER<\/b> \n<b>August, 2024<\/b> \n<b>Michele Schmitter<\/b>,&nbsp;Depression Expertise Center, Pro Persona Mental Health Care, Nijmegen, The Netherlands&nbsp;  \n<b>Reviewer Comment:<\/b> The authors performed a systematic review to study the effectiveness of exercise or physical activity interventions as an adjunct to pharmacotherapy in treatment-resistant and non-remitted depression. Although the topic is of interest to the scientific community, the article has several major shortcomings that need to be addressed before Indexing can be considered.  \n<b>General Remarks<\/b>. Please clarify ambiguous statements (e.g., page 3, line 3; page 4, outcome parameter), and use clear and concise language (e.g., page 3, line 6).  \n<b>Author Response:&nbsp;<\/b> Dear reviewer, considering all your requests, we have clarified the matter throughout the manuscript. Thank you very much for your review. Your comments have been constructive in improving the manuscript.  \n<b>Reviewer Comment:<\/b>  \n<b>Introduction<\/b>  The relevance of exercise or physical activity as an add-on therapy for NRD or TRD is not well developed. The authors should explain why exercise could be a good add-on treatment for NRD and TRD. They could use the available evidence showing that exercise is effective for MDD (e.g., Noetel et al., 2024; Morres et al., 2019) to argue that it might also be effective for NRD and TRD, but no systematic review has been conducted so far.  \n<b>Author Response:&nbsp;<\/b> Dear reviewer, thank you very much for your suggestions. We have added the recent systematic review and meta-analysis by Noetel et al. 2024 to the article's introduction. The discussion explains the cause-effect of exercise in the brain and people with MDD or anyone.    \n<b>Reviewer Comment:<\/b>  Additionally, it would be useful to define physical activity and exercise.  \n<b>Author Response:&nbsp;<\/b> Definitions for physical activity and exercise have been amended in the introduction.   &nbsp;Elaborate on the different exercise protocols and how they relate to the current evidence.  \n<b>Author Response:&nbsp;<\/b> Amended. It has been added that effective treatments (different kinds of exercise) are proportional to the intensity prescribed.   Finally, the study by Krogh et al. (2017) did not include patients with TRD and NRD.  (Krogh et al.2017).    \n<b>Author Response:<\/b> Dear reviewer, thank you for your message; we have deleted this reference from the introduction and changed the corresponding paragraph.     \n<b>Reviewer Comment:<\/b> \n<b>Methods<\/b>  Intervention: Please elaborate on the types of interventions included in this review. What kinds of interventions were included? Supervised exercise treatment, activity tracker or online modules, exercise advice, single exercise sessions, etc.?  \n<b>Author Response:<\/b> Thank you for your message. We have considered explaining more: &quot;\n<b>I<\/b>ntervention\n<b>:<\/b> any type of PA or exercise intervention that includes supervised exercise, online sessions, unsupervised activities, or recommendations.&quot;   Comparator: What kinds of control conditions were included?  \n<b>Author Response:<\/b> Thank you for your message. We have considered your proposal and written down the characteristics of the control participants.   Outcome: Other outcomes that the authors discuss later should be mentioned here.  \n<b>Author Response:<\/b> Thanks for your message; we have added some complementary information.   Study Design: Include within-person designs. However, it is unclear why the authors chose within-person designs if they only included RCTs.  \n<b>Author Response:<\/b> Dear reviewer, this information is not already in the manuscript.   Quality Appraisal: The quality appraisal is not appropriate. I recommend using other quality assessment tools (e.g., Cochrane Risk of Bias Tool).  \n<b>Author Response:<\/b> Dear reviewer, thank you for your recommendation. However, PEDro and Oxford's evidence levels are quality appraisals the journal accepts. If we change with your recommendation, we should also change all the written results related to this issue. Anyway, we will take into account your recommendation for the following work.   Selection of Studies: A table summarizing the selected studies should be included in the manuscript, not the supplements.  \n<b>Author Response:<\/b> Thank you for the suggestion. We will ask the journal's editor whether this suggestion is possible.    \n<b>Reviewer Comment: Results<\/b>  Characteristics of Studies: The provided citations are confusing. The authors state that eight of the studies are from the same project but cite all 11 studies afterward. Only those studies from the same project should be cited here.  \n<b>Author Response:<\/b> Dear reviewer. Thank you very much for your suggestion; we have changed the citations to only mention the eight regarding the same project, not the 11 ones.   The same applies to the rest of this paragraph. The authors state that two studies (i.e., Carta and Mather) used concurrent exercise interventions, and the others used &quot;traditional&quot; interventions, again citing Carta and Mather. Moreover, &quot;concurrent&quot; and &quot;traditional&quot; interventions are inappropriate in this context.  \n<b>Author Response:<\/b> Thank you for your message; we have appropriately changed the citations.   Characteristics of Exercise Interventions: &quot;The period of assessment,&quot; where the authors refer to the assessment of depressive symptoms, should be stated elsewhere. Instead, the intervention period should be mentioned here.  \n<b>Author Response:<\/b> Thank you for your message. We wanted to emphasize the exercise intervention's duration, not the evaluation period's duration. To clarify this term, we have changed the &quot;period of assessment&quot; to the &quot;period of physical activity or exercise intervention.&quot;   Meta-Analysis Statement: The statement explaining why the authors do not perform a meta-analysis is misplaced in the methods section. Please avoid using informal language.  \n<b>Author Response:<\/b> Dear reviewer. According to another reviewer's suggestion, we have also changed this paragraph in the following way: &quot;Although we understand that the meta-analysis of the different studies' results may provide objective global information on specific variables, according to the chosen articles, the data we have are insufficient to perform the statistical procedure required for meta-analysis. Further, the diversity of the primary outcomes makes it even more difficult to combine data derived from the different studies. In this sense, a systematic review allows us to include those variables related to &quot;what interests us&quot; that cannot be meta-analyzed due to insufficient cohorts or test statistics.&quot;    \n<b>Reviewer Comment: Discussion<\/b>. Since eight of the 11 studies used the same population, there are actually only three studies showing that exercise can be an effective add-on treatment to reduce depressive symptoms in TRD and NRD. Therefore, the amount of evidence is very limited, which the authors should discuss. A more hesitant optimism towards exercise as an add-on treatment for TRD and NRD would be more appropriate considering the limited evidence so far.  \n<b>Author Response:<\/b> Dear reviewer, we have changed the last paragraph of the discussion, adding what you recommend regarding the limited evidence. In this sense, we have also changed the conclusion in the abstract and manuscript.","URL":"https:\/\/f1000research.com\/articles\/12-1517\/v8#referee-comment-12243","order":3,"name":"referee-comment-12243","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.172539.r332807, Miguel Jacinto, ESECS-Polytechnic of Leiria, Leiria, 23 Oct 2024, version 4, 2 approved with reservations, 1 not approved","URL":"https:\/\/f1000research.com\/articles\/12-1517\/v4#referee-response-332807","order":4,"name":"referee-response-332807","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>SARA MALDONADO-MARTIN<\/b>; \n<i>Posted: 31 Oct 2024<\/i>; ANSWERS TO REVIEWER-\n<b>Miguel Jacinto<\/b>\n<b>-1<\/b> Physical activity in the treatment-resistance depression and non-remitted depression: a systematic review of randomized controlled trials We express our sincere gratitude for taking the time to review the manuscript and for the invaluable suggestions provided to enhance it. Following your recommendations, we have been able to improve the manuscript and have implemented the following changes:  1.The number of studies that were extracted from the search should appear in the results section of the abstract. Dear reviewer, the number of studies has been presented in the methods section. As you suggested, we will change it and present it in the results section.  2. The keywords should be different to the words used in the title. Amended. Repeated keywords have been replaced  3. Disorder is different from disability. Dear reviewer. Agree with you in your assertion. However, we want to say that the major depressive disorder may lead to disability. In the present disorder, people with major depression may suffer a functional disadvantage affected by that condition. To clarify, we have changed the second part of the sentence- Major depressive disorder (MDD) is one of the most prevalent mental illnesses in the world, which may lead to disability.  4.&nbsp;What hypotheses are being studied? Dear reviewer, as you know, a hypothesis is not strictly necessary in a systematic review as in an experimental study. However, it can be helpful. Therefore, as you suggested, we have added a hypothesis at the end of the introduction.  5. The introduction does not make it clear to the author what gap in the literature the authors aim to fill. Dear reviewer, to date, there are no systematic reviews showing results according to the effects of physical activity and exercise on people with Treatment-resistant depression. There are some studies but no systematic review. We think that it is important to show that exercise is also a valuable tool in this population.  6.&nbsp;What does this study add to the literature? Dear reviewer, this study aims to examine the effects of exercise interventions in people with TRD and NRD. This population is relatively small, and as noted in the review, interventions involving exercise are limited. This review offers important contributions to the existing literature and concludes that exercise may improve the condition. However, further research in this area is necessary to strengthen the evidence.  7. Did the authors strictly follow the protocol submitted to PROSPERO? Yes, the systematic review is registered as CRD42022298347 and was accepted for implementation by Prospero, and we followed the submitted protocol.  8. Were studies with sports interventions excluded? Thank you for your comment. As explained in the section on PICOS questions, we searched for and included any intervention involving physical activity or exercise. However, interventions involving sports were not considered or included in the search strategy. To clarify, we have added a sentence related to this issue.  9. What is the difference between the two types of studies included in the review? Randomized trials may sometimes omit the control group and conduct multiple groups with different types of treatment as opposed to RCTs, which are studies in which there is a control group.  10. Why were only these two types of studies included? To include randomized clinical studies in a systematic review is important for several reasons:  Minimization of bias: Randomization helps reduce selection and confounding bias, allowing the intervention and control groups to be comparable at the start of the study. Greater internal validity: Randomized studies generally offer greater internal validity, meaning that the results are more reliable and can be attributed with greater certainty to the evaluated intervention. More robust evidence: Including randomized trials provides a solid basis for making clinical recommendations, as these studies are considered the gold standard for evaluating the effectiveness of an intervention. Consistency in quality: By focusing on randomized controlled trials, consistency in the methodological quality of the included studies is ensured, which facilitates comparison of results. Better generalizability: Although generalizability may be limited, well-designed RCTs tend to have a more representative sample of the general population, allowing better extrapolation of findings.  For these reasons, systematic reviewers prefer to focus on randomized studies to obtain more robust and reliable conclusions about the efficacy of an intervention.  11. The eligibility criteria should be written in more detail. Dear reviewer, we have used the PICOS strategy, and all the components have been specifically explained. If you think that something is missing, we would appreciate more information.  12.The start and end date of the literature search are unclear. Thank you for your comment. In the Data Sources and Search Strategy section, we provided information regarding your question: A systematic literature search was conducted in June 2024. During that month, the search and selection of articles were carried out.  13. It is not clear when the studies searched were conducted. We have answered this question in the previous one.  14.&nbsp;What is the reason for choosing these databases? We consider these databases among the most widely utilized in our scientific field, and we believe that by incorporating five reputable databases, we would successfully meet the objectives of this systematic review.  15. Why is the search different in the databases? In each database, the search strategy has been adjusted because Boolean operators such as AND\/OR function differently across the platforms.  16. The reason for removing items from the PEDro scale is unclear. Dear reviewer, removing items 5 and 7 from the PEDro scale in a systematic review might be justified for several reasons:  \n<b>Item 5 (Blinding of Participants)<\/b>: If blinding participants is deemed impractical or irrelevant to the specific intervention being studied, it could be argued that this item does not significantly impact the study's findings. \n<b>Item 7 (Blinding of Assessors)<\/b>: Similar to item 5, if the nature of the intervention or outcome measurement does not allow for blinding of assessors (e.g., subjective outcomes) or if it has been shown that assessors\u2019 bias does not significantly affect results, this item may be considered less critical.  Removing these items might be based on a rationale that the overall integrity of the reviewed studies remains intact despite the absence of these specific quality indicators.  17. The authors could proceed to carry out a meta-analysis. Dear reviewer, thank you for your comment. However, according to the chosen articles, our data are insufficient to perform the statistical procedure required for meta-analysis. Further, the diversity of the primary outcomes makes it even more difficult to combine data derived from the different studies. An explanation regarding this issue is presented in the results.  18. What tool was used to assess the risk of bias? Dear reviewer, we have used the PEDro scale to appraise the quality of evidence in clinical trials. Higher scores indicate a lower risk of bias and more reliable findings. It is true that while this scale addresses important methodological aspects, it does not cover all potential sources of bias.","URL":"https:\/\/f1000research.com\/articles\/12-1517\/v8#referee-comment-12756","order":5,"name":"referee-comment-12756","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.200392.r497994, Gerasimos N. Konstantinou, Centre of Addiction and Mental Health, Toronto, 06 Jul 2026, version 8, indexed","URL":"https:\/\/f1000research.com\/articles\/12-1517\/v8#referee-response-497994","order":6,"name":"referee-response-497994","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":7,"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"}]}}