{"paper_id":"1960fe4b-9f63-40b5-b372-578caebf2082","body_text":"Treatment with combined exercise in patients with resistant major depression (TRACE-RMD): study protocol for a randomized clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Treatment with combined exercise in patients with resistant major depression (TRACE-RMD): study protocol for a randomized clinical trial Nagore Iriarte-Yoller, Jose Echaniz-Oses, Cristobal Pavón-Navajas, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4946519/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Dec, 2024 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background Around 40% of people with major depressive disorder (MDD) experience moderate remission, with the remainder meeting the criteria for resistant major depression (RMD). It has been shown that exercise has a low-to-moderate effect on MDD, but there is a lack of evidence on exercise interventions in RMD patients. The primary purpose of the proposed study will be to investigate the effect of a 12-week supervised combined exercise program on depressive symptoms in people with RMD compared to a treatment-as-usual (TAU) group. Method This randomized, single-blind, controlled experimental trial will include 70 adults (≥ 18 years old) with RMD. Participants randomized to an exercise intervention or a TAU group will be assessed at baseline and after a three-month intervention period. The primary variable will be participants’ depressive symptoms measured with the Montgomery-Asberg Depression Rating Scale. Secondary outcome variables will include cardiorespiratory fitness (peak oxygen uptake through peak cardiopulmonary exercise test), body composition (bioimpedance and anthropometric variables), physical activity level (the International Physical Activity Questionnaire), health-related quality of life (the Short Form – 36 Health Survey), functional outcome (the Sheehan Disability Scale and Quality of Life in Depression Scale), overall disease severity (the Clinical Global Impression Scale – Severity of Illness), and biochemical variables (a fasting blood sample). Discussion This study will try to answer whether a supervised co-adjuvant combined (aerobic and resistance training) exercise program will help the prognosis of this population with RMD. Trial registration ClinicalTrials.gov, identifier NCT05136027. Last public release on 12/13/2023 Resistant Major Depression exercise quality of life combined training Figures Figure 1 Figure 2 Introduction Major depressive disorder (MDD) is one of the most prevalent mental disorders worldwide and one of the most disabling, affecting more than 300 million people global ( 1 ). Thus, MDD is a complex multifactorial condition that includes complex pathophysiology and creates neural and neurotransmitter inflammation ( 1 , 2 ). In addition to depressive symptoms, people with MDD tend to lead an unhealthy lifestyle including a lack of physical activity, sedentary behaviour, smoking, abuse of alcohol, and poor diet, resulting in various cardiovascular-related diseases ( e.g. , coronary heart disease, obesity, diabetes mellitus type 2, and stroke) ( 3 ). Physiologically, people suffering from MDD are associated with increased immune system activation, leukocyte function, and release of proinflammatory cytokines such as interleukins (IL) 1, 2, and 6 ( 1 ). Therefore, the combination of pharmacological treatment ( i.e. , a variety of antidepressants) and psychological therapies for the treatment of MDD is insufficient. In this sense, around 40% of people with MDD experience moderate remission, with the remainder meeting the criteria for resistant major depression (RMD) ( 4 ). The typical treatment for this population consists of a pharmacological intervention using first- and second-generation antidepressant drugs that act on the brain synapse to increase the bioavailability of amines ( i.e. , serotonin, noradrenaline, and dopamine) ( 5 ). However, only one-third of people achieve remission after initial treatment ( 5 ). Hence, RMD is defined as an inadequate response to at least two different antidepressants of appropriate dose and duration ( 6 ). Given this bleak outlook, several non-pharmacological strategies have been considered as possible co-adjuvant interventions to help improve the prognosis and remission rates of RMD, such as neurosurgical intervention, somatic therapies, electroconvulsive therapy, or even adjunctive strategies, among which exercise is one of the most important ( 7 ). It has been shown that exercise has a low-to-moderate amelioration effect on MDD, with response rates comparable to mainstream therapies like antidepressant medication and cognitive behavioural therapy ( 1 , 8 ). The latest World Health Organization guidelines on physical activity and sedentary behaviour include evidence-based public health recommendations for people living with chronic conditions like mental disorders. Thus, adults should perform 150–300 min per week of moderate-intensity physical activity and two days of muscle-strengthening activity ( 9 ). However, some controversy still exists about the FITT (frequency, intensity, time, and type) principle and the latest scientific advances in exercise training for people with RMD. In most studies conducted with this population, the exercise interventions included 1 hour per session, two days per week, and more than 10 weeks of endurance intervention ( 10 , 11 ), performed on a cycle ergometer or treadmill ( 10 , 12 ), Only one study conducted a combined intervention, including endurance and resistance training ( 12 ). Previous studies have shown that low-to-moderate intensity training is an efficient method to improve different outcomes like cardiorespiratory fitness (CRF) and body mass index (BMI) in adult populations with chronic diseases, especially for individuals with a low initial level of aerobic fitness ( 13 , 14 ). Considering the above, here we propose the TRACE-RMD study to investigate the effects of a 12-week supervised combined exercise program ( i.e. , aerobic and resistance exercises in the same session) for people with RMD in comparison with a treatment-as-usual (TAU) control group doing occupational activity sessions with the same frequency and duration as the exercise group. Thus, the main aim of this randomized controlled trial will be to analyse the effects of a combined exercise program on depressive symptoms compared to a TAU group. The secondary objectives will be 1) to analyse the program’s effects on CRF, body composition, and biochemical levels and 2) to determine changes in the functional outcome, overall disease severity, and quality of life of participants. Methods Study design, ethical approval, and registration The TRACE-RMD study will be a randomized, single-blind ( i.e. , medical specialists will evaluate the psychiatric variables) controlled experimental trial. The study protocol was written per the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines( 15 ) and the updated SPIRIT 2024 and CONSORT 2024 reporting guidelines ( 16 ), aiming to improve the quality of the intended clinical trial. Participants: Recruitment and selection criteria Specialized psychiatrists from the Resistant Depression Unit of the Álava Psychiatric Hospital and Álava Mental Health Network (Basque Country, Spain) will recruit 70 adults with RMD, which provides psychiatric care to the population living in the community and encourage participation by explaining the benefits of exercise as an adjuvant programme in their treatment. The inclusion and exclusion criteria for the TRACE-RMD study are shown in Table 1 . Table 1 Inclusion and exclusion criteria for the TRACE-RMD study. Inclusion criteria - ≥ 18 years old. - Patients living in the community or hospitalized patients. In the two cases, the RMD diagnosis is defined as the person who receives the treatment does not have a remission, with a poor or unsatisfactory response to at least two adequate (i.e., optimal dosage and duration) different antidepressants. However, previous research studies have demonstrated the lack of consensus criteria in defining RMD.(6) - Treatment-resistant depression is defined as resistance to two or more antidepressants. - Written informed consent has been signed. Exclusion criteria - Schizophrenia or other psychoses. - Presence of imminent suicidal risk. - Unstable or inadequately controlled medical illnesses (in acute pathology situations). - Active substance use disorder. - Comorbidity with other psychiatric pathologies constitutes the main focus of treatment. - Cognitive impairment anchored by the Montreal Cognitive Assessment scale < 26/30. - Inability to perform exercise secondary to osteoarticular, cardiovascular or metabolic difficulties. - Performing exercise continuously as a regular practice. ≥, greater than or equal to; RMD: Resistant mayor depression. Participants will be free to withdraw from the study at any time. The participant may not continue in the study for the following reasons: 1) failure to maintain 80% compliance with training sessions (minimum 19 sessions); 2) missing more than two consecutive training sessions; 3) the participant's condition or disease progresses; 4) the participant experiences a severe adverse event ( e.g. , angina, dyspnoea, dizziness) that requires discontinuation or withdrawal from the study in accordance with the study protocol; or 5) pregnancy. Randomization After the informed consent is accepted and signed, the participants will be included in the trial by being given a trial-specific anonymous identification ( i.e. , TRACE-01) number (ID). Allocation consignment will be performed by a technician from Bioaraba Research Institute ( http://aleatorizacion.bioaraba.org/ ) using the technique of stratified randomization (1:1) by sex (men/women) and depressive symptoms. The participants will be randomized to one of the two intervention groups: 1) the exercise (EX) group and 2) the TAU group. Exercise physiologists will be responsible for informing each participant of the group in which they will participate. Figure 1 presents a flow diagram of the study process. Outcomes and measurements Data collection will be based on an assessment protocol for gathering data on physical, clinical, and biochemical variables. Assessments used in the protocol will be evaluated before (T0) and after a 12-week intervention period (T1). Participants from the two groups will be assessed concurrently. Sociodemographic data (including participant sex, age, state of convivence, professional status, drug and smoking status, age of onset of illness, number of hospitalizations, date of last hospitalization, medication intake, and treatment duration) will be collected before the baseline assessment. Measurements will be performed in three separate visits according to the sequence: Visit 1: functional outcome and quality of life with questionnaires. Visit 2: anthropometry, body composition and cardiopulmonary exercise test (CPET). Visit 3: fasting blood sample The primary outcome (depressive symptoms) will be measured with the Montgomery-Asberg Depression Rating Scale (MADRS) using the validated Spanish version ( 17 ). Secondary outcome variables will include CRF, body composition, biochemical and functional outcomes, and quality of life. The SPIRIT figure showing the time points for assessments and intervention is shown in Fig. 2. The MADRS is a clinical interview with extended phrased questions about symptoms of depression and anxiety. The questionnaire has 10 different items about depression. Adding up scores can be obtained between 0 (zero; absence of depression) and 60 (major level of depression) ( 17 ). For evaluating functionality, the Sheehan Disability Scale (SDS)( 18 ) and the Spanish version of the Quality of Life in Depression Scale (QLDS) ( 19 ) will be used. The copyright license agreement for the SDS was obtained through Dr. David V. Sheehan, and it included a Spanish linguistic validation. The SDS is a subjective scale with three items (social, family, and work) evaluating the incapacity o depression ( 20 ), and the QLDS is a depression-specific quality of life scale based on the possibility and capacity of the individual to satisfy the particular needs ( 19 ). The overall disease severity will be measured using the Clinical Global Impression Scale – Severity of Illness (CGI-SI). The CGI-SI is a descriptive, hetero-applied scale that provides qualitative information on the severity of the clinical condition and the change experienced by the patient concerning the baseline condition in three different measures ( i.e. , illness severity, global improvement, and efficacy index) ( 21 , 22 ). Anthropometry will include stature (SECA 213, Hamburg, Germany), total body mass (SECA 869, Hamburg, Germany) BMI calculated as total body mass (kg)/stature (m 2 ), and waist and hip circumferences calculated with waist-to-hip ratio (SECA 200, Hamburg, Germany). All measurements will follow the International Society for the Advancement of Kinanthropometry guidelines ( 23 ). Furthermore, bioelectrical impedance analysis will estimate fat-free mass, total body water, and fat mass (Tanita, BF 350, and Tanita, BC-418 MA, Amsterdam, the Netherlands). The International Physical Activity Questionnaire (IPAQ) will assess physical activity level and sedentary behaviour. This questionnaire has seven items, and the participant should respond on their ownbase over the prior seven days ( 24 ). The Spanish version of the Short Form – 36 Health Survey (SF-36) will assess participants’ health-related quality of life. The SF-36 is a short questionnaire with 36 items of eight dimensions of items, including physical functioning, social functioning, role limitations attributed to physical problems, role limitations attributed to emotional problems, mental health, vitality, pain, and general health perception ( 25 ). The CRF assessment will involve a symptom-limited CPET on a bike ergometer (Lode Excalibur, Groningen, the Netherlands). The protocol will commence at 40 W, with gradual increments of 10 W per min until exhaustion while continuously monitoring an electrocardiogram. The gas analyser (Ergo CardMedi-soft S.S, Belgium Ref. USM001 V1.0) will undergo calibration before each test. Peak oxygen uptake (VO 2peak ) will be defined as the highest oxygen consumption value achieved after the test. Peak effort will be acknowledged when meeting at least two or more of the following criteria: participant fatigue (Borg scale > 18), respiratory exchange ≥ 1.1, attainment of > 85% of predicted maximum heart rate (HR), and no increase in VO 2 and/or HR with escalating workload ( 26 ). After each minute, the subjective sensation of exertion will be documented using the original Borg scale ( 27 ). Blood pressure (BP) will be assessed at two-minute intervals throughout the test. Ventilatory thresholds (VTs) will be evaluated through standardized methodologies employing V-slope and ventilatory equivalents (EqV). The first ventilatory threshold (VT 1 ) will be determined when the inflection point in the carbon dioxide production (VCO2) versus VO2 slope transitions from less than 1 to greater than 1. Alternatively, it can be identified as the nadir in the EqV ratio of VO 2 versus workload. The second ventilatory threshold (VT 2 ) will be pinpointed as the nadir in the EqV/VCO 2 ratio versus workload ( 26 ). After completing the test, the participant will remain at rest on the bicycle for an additional 5 min to record recovery variables. All absolute and relative criteria for concluding the test will be duly considered. The intensity ranges will be individually tailored based on HR to establish light (ranging from a resting HR value to an HR value of the VT 1 ) and moderate (HR value between VT 1 and VT 2 ) intensity categories: specifically, R1 – light to moderate intensity with HR values below VT 1 ; R2 – moderate-to-high intensity with HR values between VT 1 and VT 2 ; and R3 – intense-to-severe intensity with HR values above VT 2 up to peak HR. Biochemical profiles will be determined with a fasting blood sample (10 mL) collected at the hospital for each participant after an overnight fast, including the following parameters: haemoglobin, haematocrit, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, C-reactive protein, uric acid, creatinine, sodium, potassium, and albumin. HOMA-IR will be used to evaluate insulin resistance ( i.e. , fasting serum insulin [µU/mL] × fasting plasma glucose [mg/dL] / 405) ( 28 ). Moreover, cytokine levels in IL-1, IL-6, and IL-10 plasma levels will be measured via enzyme immunoassays. Study intervention The participants enrolled in the EX group will undergo a 12-week exercise program (two non-consecutive days per week) under the supervision of exercise specialists at out-of-hospital facilities ( i.e. , the Physical Activity for Health Research Center). All sessions will start and end with BP measurements, and exercise intensity will be monitored by HR monitors (Polar Electro, Kempele, Finland) and through the original Borg scale ( 6 – 20 ). Each session will include a 10 min warm-up and a 10 min cool-down with stretching. The main part of the session will consist of a four-part circuit of 10 min each: 1) a low-volume and low-intensity interval training (LV-LIIT) exercise on the bicycle (Table 2 ); 2) strength-resistance exercises (elastic bands, own body weight, dumbbells [Additional file 1]); 3) an LV-LIIT exercise on the bicycle (Table 2 ); and 4) lumbopelvic strengthening exercises (Additional file 1). During the sessions, the power and speed of the bike will be adjusted to achieve the target HR. In the LV-LIIT exercise, participants will warm up for 2 min and then engage in six intervals of 15 s at R2 interspersed with 1-min intervals at R1, finishing with 2 min of cool-down at R1 (Table 2 ). In the resistance workout, the participants will perform a time-based circuit (30 s per exercise, with 30 s rest) of 10 strength-resistance exercises, including both upper and lower body, covering the main muscle groups and coordinated with breathing. In the lumbopelvic strengthening workout, the participants will carry out six exercises (20 repetitions with 20 s of rest between each exercise), including the anterior and posterior musculature (Additional file 1). Some strategies will be used to achieve adherence, such as individualized attention while exercising and telephone calls following missed sessions. The TAU group will conduct a standard practice and continue with their regular treatment plus occupational activities (inpatient) for the same duration as the intervention in the EX group. Due to RMD, it is not necessary to instruct participants not to engage in any other activity involving exercise because the difficulty involves them in the project. To promote retention in the project, after completion of the post-intervention assessments, all participants are offered an exercise programme within the hospital (unrelated to the research). Table 2 Exercise intervention through low-intensity interval training on a cycle ergometer Protocol Moderate-intensity interval training Low-intensity interval training Weeks Volume (min) Intensity (%HR res ) Weeks Volume (min) Intensity (%HR res ) 1–4 3 60 1–4 17 50 5–8 3 65 5–8 17 55 9–12 3 70 9–12 17 60 In case of adverse events will be recorded and reported to the corresponding Ethics Committee. Data management All data recording will be carried out by the lead research psychiatrist (NIY) and the persons responsible for the exercise programme (JEO & MTE). The database shall be coded, and only the persons responsible for the research will have access to it. Upon completion of the study, the results will be published and presented to social media, academics, and clinical institutions. Likewise, research articles will be submitted to peer-reviewed journals and presented at relevant scientific conferences. Sample size estimation Based on a previous pilot study with the same population, to achieve a power of 80% where differences in depressive symptoms (measured by the MADRS) are detected after the exercise intervention, having a significance of 5%, a reference mean of 29.13 ± 12.2 units, an experimental group mean of 22.23 units, a standard deviation between both groups of 9.61, and an expected difference of 2.5 units, 31 patients per group will be needed. If we assume a 10% loss rate, 35 patients per group will be required, with a total sample of 70 participants. Statistical analysis A general descriptive analysis of the sample will be performed to assess baseline homogeneity. The Kolmogorov-Smirnov test will determine the normality of quantitative variables, and results will be expressed as means and standard deviations or as median values and interquartile ranges in the case of non-normal distributions. Qualitative variables will be expressed as frequencies and percentages. Student’s t -test for related samples will be carried out to assess the impact of the intervention on quantitative variables. A nonparametric analog Wilcoxon will be chosen if it does not meet normality criteria. A covariate analysis (ANCOVA) will evaluate change after the intervention, considering the two EX and TAU groups ( i.e. , independent variable). The magnitude of the differences will be assessed using 95% confidence intervals and Hedges's g effect sizes. During the development of the study, deviations from the protocol may arise. The statistical analysis will be performed via intention-to-treat and protocol to manage these situations within the study. The TRACE-RMD study does not have a data monitoring committee, and the Ethical Committee does not require it, given the project is under constant review of the psychiatry specialists. No interim analyses are planned. Discussion This study will be the first clinical trial to explore the efficacy of a combined exercise intervention as a potential co-adjuvant to pharmacological treatment in patients with an RMD diagnosis. Recent meta-analyses have shown that different types and dose-responses of exercises like walking, aerobic training, Yoga, Qigong, resistance training, and Tai Chi have effectively alleviated depressive symptoms in older adults ( 29 ), and adults in general ( 30 ). Therefore, since RMD populations can be resistant to two or more antidepressants ( 6 ), exercise interventions should be considered an effective adjuvant program in the treatment of RMD. In this sense, the appropriate FITT principle of exercise interventions remains unclear, and controversy exists ( 31 , 32 ). Moreover, although a significant percentage of interventions are aerobically oriented, a recent meta-analysis revealed moderate antidepressant effects of strength training in people with a diagnosis of depression or depressive symptoms ( 33 ). Therefore, combined training ( i.e. , aerobic + resistance training in the same session) could be considered a powerful option to investigate in people with RMD. Thus, previous studies have implemented and analysed exercise interventions in people with RMD ( 10 – 12 , 34 ). While these interventions have shown improvements in psychiatric variables, enhancing psychopathological symptoms like depression, functionality, and even quality of life, none has implemented a combined exercise training intervention or analysed potential physical, objective physiological, and biochemical improvements in this population. In this regard, given that the improvement in CRF through exercise training has led to enhanced health and reduced mortality in people with severe mental illness ( 35 ), to analyse this variable is crucial. Furthermore, the biochemical analysis will provide the opportunity to examine IL-6 and IL-1, which have been associated with the onset of proinflammatory inflammation and are particularly relevant in the brain ( 36 – 38 ). In line with this, peripheral cytokines can cross the blood-brain barrier and reach the central nervous system, provoking neuroinflammation, which might trigger psychiatric disorders such as depression ( 39 ). Therefore, analysing these ILs will be pertinent, as exercise interventions have been shown to decrease IL-6 levels ( 40 ). Overall, this research will provide further information and build upon previous findings regarding a co-adjunctive strategy (combined exercise training) in individuals diagnosed with RMD. Trial Status The trial was initially released as a pilot study (no clinical trial) on 24th November 2021 (version 1). The present manuscript is based on the 18th December 2023 trial protocol (version 2). Recruitment of participants started in January 2024 and is estimated to be completed up to December 2025. Abbreviations BMI Body Mass Index BP Blood Pressure CGI-SI Clinical Global Impression Scale-Severity of Illness CPET CardioPulmonary Exercise Test CRF CardioRespiratory Fitness EqV Ventilatory Equivalent EX exercise FITT Frequency, Intensity, Time and Type HR Heart Rate IL InterLeukin IPAQ International Physical Activity Questionnaire LV-LIIT Low-Volume and Low-Intensity Interval Training MADRS Montgomery-Asberg Depression Rating Scale MDD Major Depressive Disorder QLDS Quality of Life in Depression Scale RMD Resistant Major Depression SDS Sheehan Disability Scale SF-36 Short Form-36 Health Survey TAU Treatment As Usual VCO 2 Carbon Dioxide Production VO 2peak Peak Oxygen Uptake VT Ventilatory Threshold Declarations Ethics approval and consent to participate The design of the study conforms to the principles outlined in the Declaration of Helsinki, and the protocol, together with the informed consent procedures of the TRACE-RMD study, were approved by the Ethics Committee of Investigation of the local Hospital (11 May 2023, Certificate No. 2023-008). The protocol was registered with the United States National Library of Medicine (Clinical Trials.gov ID no. NCT05136027). Participants will be fully informed of the aims and procedures of the research before collecting their informed consent and before the clinical and physiological examination. Each participant will be allowed to ask questions about the investigation. Consent for publication. Not applicable Competing interest. The authors declare that they have no competing interests. Funding This project was funded by the \"III Convocatoria Intramural de la Fundación Vital Fundazioa – IIS BIOARABA\" and the Mental Health Network of Álava. Authors’ contributions All authors read and approved the final manuscript. Conception of the project (NIY, JEO, CPN, MTE, PMSG, SMM, EEZ). Design of the work and methodology (NIY, JEO, CPN, MTE, PMSG, SMM, ABYE, EEZ). Availability of data ana materials The data will be available from the corresponding author upon reasonable request. 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Tang L, Zhang L, Liu Y, Li Y, Yang L, Zou M, et al. Optimal dose and type of exercise to improve depressive symptoms in older adults: a systematic review and network meta-analysis. BMC Geriatr 2024 Jun 7;24(1):505–7. Noetel M, Sanders T, Gallardo-Gómez D, Taylor P, Del Pozo Cruz B, van den Hoek D, et al. Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials. BMJ 2024 Feb 14;384:e075847–075847. Contreras-Osorio F, Ramirez-Campillo R, Cerda-Vega E, Campos-Jara R, Martínez-Salazar C, Reigal RE, et al. Effects of Physical Exercise on Executive Function in Adults with Depression: A Systematic Review and Meta-Analysis. IJERPH 2022 -11-18;19(22). Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB. Physical activity interventions for people with mental illness: a systematic review and meta-analysis. J Clin Psychiatry 2014 Sep;75(9):964–974. Rossi FE, Dos Santos GG, Rossi PAQ, Stubbs B, Barreto Schuch F, Neves LM. 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The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999 Jul;4(4):317–327. Dantzer R, Wollman E, Vitkovic L, Yirmiya R. Cytokines and depression: fortuitous or causative association? Mol Psychiatry 1999 Jul;4(4):328–332. Réus GZ, Manosso LM, Quevedo J, Carvalho AF. Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities. Neurosci Biobehav Rev 2023 Dec;155:105425. Legård GE, Pedersen BK. Chapter 13 - Muscle as an Endocrine Organ. In: Zoladz JA, editor. Muscle and Exercise Physiology: Academic Press; 2019. p. 285–307. Supplementary Files SPIRITchecklist.docx Additionalfile1resistancetrainingprogram.pdf Cite Share Download PDF Status: Published Journal Publication published 18 Dec, 2024 Read the published version in Trials → Version 1 posted Editorial decision: Major revision 04 Nov, 2024 Reviewers agreed at journal 03 Nov, 2024 Reviewers invited by journal 01 Nov, 2024 Editor assigned by journal 29 Aug, 2024 First submitted to journal 23 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-4946519\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":372979656,\"identity\":\"a38004ab-44a2-4d63-af85-c66068a94108\",\"order_by\":0,\"name\":\"Nagore Iriarte-Yoller\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Osakidetza Basque Health Service. Araba Mental Health Network\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Nagore\",\"middleName\":\"\",\"lastName\":\"Iriarte-Yoller\",\"suffix\":\"\"},{\"id\":372979657,\"identity\":\"4be27ffc-aee2-4496-921c-60e0ffd8dac5\",\"order_by\":1,\"name\":\"Jose Echaniz-Oses\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"UNIVERSITY OF THE BASQUE COUNTRY (UPV/EHU)\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jose\",\"middleName\":\"\",\"lastName\":\"Echaniz-Oses\",\"suffix\":\"\"},{\"id\":372979658,\"identity\":\"939f09f1-35b2-4459-801c-67d30160a032\",\"order_by\":2,\"name\":\"Cristobal Pavón-Navajas\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Osakidetza Basque Health Service. Araba Mental Health Network\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Cristobal\",\"middleName\":\"\",\"lastName\":\"Pavón-Navajas\",\"suffix\":\"\"},{\"id\":372979659,\"identity\":\"ece12858-875b-46cc-97a9-257f95dd4f80\",\"order_by\":3,\"name\":\"Mikel Tous-Espelosin\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"UNIVERSITY OF THE BASQUE COUNTRY (UPV/EHU)\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mikel\",\"middleName\":\"\",\"lastName\":\"Tous-Espelosin\",\"suffix\":\"\"},{\"id\":372979660,\"identity\":\"d9d04b29-d50f-4fb9-a3f3-ed0efc8cc751\",\"order_by\":4,\"name\":\"Pedro M. Sánchez-Gómez\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Osakidetza Basque Health Service. Bizkaia Mental Health Network\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Pedro\",\"middleName\":\"M.\",\"lastName\":\"Sánchez-Gómez\",\"suffix\":\"\"},{\"id\":372979661,\"identity\":\"0d5e9f98-e168-467d-87ca-d244d8878c38\",\"order_by\":5,\"name\":\"SARA MALDONADO-MARTIN\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYBADGYYDQJKHwYbBgFgtPFAtaaRrOUxYi3z72YcfGHPsePiO9x788KbivJy5RALjY54/uLUYnEk3lmDclswjeeZcsuScM7eNLWckMBvztuHRAnQ9UAszj8GNHANp3rbbiRtuJLBJ8zbgcVj/M+YfjNvqQVqMf/O2nasHamH/jc9hDDfS2IC2HAZpMQPaciDBAGgLMw8bHofdeMZmkbjtONAvZ8ws55xJNtxw5mGz5Fw8fpHvT2O+8XFbtRzf8R7jG28q7OQNjicDgw6fw0AgAZXL2EBA/SgYBaNgFIwCQgAAnuZQMx4WZ2oAAAAASUVORK5CYII=\",\"orcid\":\"https://orcid.org/0000-0002-2622-5385\",\"institution\":\"UNIVERSITY OF THE BASQUE COUNTRY\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"SARA\",\"middleName\":\"\",\"lastName\":\"MALDONADO-MARTIN\",\"suffix\":\"\"},{\"id\":372979662,\"identity\":\"fa7991b4-d1de-4394-8d4c-7acddfc0a260\",\"order_by\":6,\"name\":\"Ana B. Yoller-Elburgo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Osakidetza Basque Health Service. Araba Mental Health Network\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ana\",\"middleName\":\"B.\",\"lastName\":\"Yoller-Elburgo\",\"suffix\":\"\"},{\"id\":372979663,\"identity\":\"86ea9321-0ea7-4627-81b1-dd3a82e965e0\",\"order_by\":7,\"name\":\"Edorta Elizagarate-Zabala\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Osakidetza Basque Health Service. Araba Mental Health Network\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Edorta\",\"middleName\":\"\",\"lastName\":\"Elizagarate-Zabala\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-08-20 16:31:29\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-4946519/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-4946519/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s13063-024-08685-7\",\"type\":\"published\",\"date\":\"2024-12-18T15:57:33+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":70296793,\"identity\":\"2bc7326f-52e6-4d8e-b387-e8aa0eaf7692\",\"added_by\":\"auto\",\"created_at\":\"2024-12-02 00:40:18\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":200085,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eFlow diagram of the TRACE-RMD study.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1.FlowchartTRACERMD.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4946519/v1/c48241fa845988651ed370ea.jpg\"},{\"id\":70296790,\"identity\":\"502ff340-63a4-41c7-9257-28c0ae96fc2d\",\"added_by\":\"auto\",\"created_at\":\"2024-12-02 00:40:18\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":257708,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe SPIRIT figure shows an overview of the assessment schedule at baseline sand follow-up in the TRACE-RMD study.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2.SPIRITfigure.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4946519/v1/f38563081f994e29da11c47b.jpg\"},{\"id\":72201823,\"identity\":\"f041cd4e-821d-4b5d-89f4-0a8f0c1f12d9\",\"added_by\":\"auto\",\"created_at\":\"2024-12-23 16:10:46\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":985505,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4946519/v1/b5f9840f-60e8-4355-b0de-b835245a7f02.pdf\"},{\"id\":70296788,\"identity\":\"46eea6e5-2ea3-4607-9b30-955780f298f3\",\"added_by\":\"auto\",\"created_at\":\"2024-12-02 00:40:18\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":42395,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"SPIRITchecklist.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4946519/v1/57e88e69e8b81affe5fc7489.docx\"},{\"id\":70296792,\"identity\":\"922f27a4-719a-45a7-a97d-97b8ca70b88a\",\"added_by\":\"auto\",\"created_at\":\"2024-12-02 00:40:18\",\"extension\":\"pdf\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":1073380,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Additionalfile1resistancetrainingprogram.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4946519/v1/9de35ae0aad775d5f7cefb6a.pdf\"}],\"financialInterests\":\"\",\"formattedTitle\":\"Treatment with combined exercise in patients with resistant major depression (TRACE-RMD): study protocol for a randomized clinical trial\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eMajor depressive disorder (MDD) is one of the most prevalent mental disorders worldwide and one of the most disabling, affecting more than 300\\u0026nbsp;million people global (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e). Thus, MDD is a complex multifactorial condition that includes complex pathophysiology and creates neural and neurotransmitter inflammation (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn addition to depressive symptoms, people with MDD tend to lead an unhealthy lifestyle including a lack of physical activity, sedentary behaviour, smoking, abuse of alcohol, and poor diet, resulting in various cardiovascular-related diseases (\\u003cem\\u003ee.g.\\u003c/em\\u003e, coronary heart disease, obesity, diabetes mellitus type 2, and stroke) (\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e). Physiologically, people suffering from MDD are associated with increased immune system activation, leukocyte function, and release of proinflammatory cytokines such as interleukins (IL) 1, 2, and 6 (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e). Therefore, the combination of pharmacological treatment (\\u003cem\\u003ei.e.\\u003c/em\\u003e, a variety of antidepressants) and psychological therapies for the treatment of MDD is insufficient. In this sense, around 40% of people with MDD experience moderate remission, with the remainder meeting the criteria for resistant major depression (RMD) (\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eThe typical treatment for this population consists of a pharmacological intervention using first- and second-generation antidepressant drugs that act on the brain synapse to increase the bioavailability of amines (\\u003cem\\u003ei.e.\\u003c/em\\u003e, serotonin, noradrenaline, and dopamine) (\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e). However, only one-third of people achieve remission after initial treatment (\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e). Hence, RMD is defined as an inadequate response to at least two different antidepressants of appropriate dose and duration (\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e). Given this bleak outlook, several non-pharmacological strategies have been considered as possible co-adjuvant interventions to help improve the prognosis and remission rates of RMD, such as neurosurgical intervention, somatic therapies, electroconvulsive therapy, or even adjunctive strategies, among which exercise is one of the most important (\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e). It has been shown that exercise has a low-to-moderate amelioration effect on MDD, with response rates comparable to mainstream therapies like antidepressant medication and cognitive behavioural therapy (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e The latest World Health Organization guidelines on physical activity and sedentary behaviour include evidence-based public health recommendations for people living with chronic conditions like mental disorders. Thus, adults should perform 150\\u0026ndash;300 min per week of moderate-intensity physical activity and two days of muscle-strengthening activity (\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e). However, some controversy still exists about the FITT (frequency, intensity, time, and type) principle and the latest scientific advances in exercise training for people with RMD.\\u003c/p\\u003e \\u003cp\\u003eIn most studies conducted with this population, the exercise interventions included 1 hour per session, two days per week, and more than 10 weeks of endurance intervention (\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e), performed on a cycle ergometer or treadmill (\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e), Only one study conducted a combined intervention, including endurance and resistance training (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e). Previous studies have shown that low-to-moderate intensity training is an efficient method to improve different outcomes like cardiorespiratory fitness (CRF) and body mass index (BMI) in adult populations with chronic diseases, especially for individuals with a low initial level of aerobic fitness (\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eConsidering the above, here we propose the TRACE-RMD study to investigate the effects of a 12-week supervised combined exercise program (\\u003cem\\u003ei.e.\\u003c/em\\u003e, aerobic and resistance exercises in the same session) for people with RMD in comparison with a treatment-as-usual (TAU) control group doing occupational activity sessions with the same frequency and duration as the exercise group. Thus, the main aim of this randomized controlled trial will be to analyse the effects of a combined exercise program on depressive symptoms compared to a TAU group. The secondary objectives will be 1) to analyse the program\\u0026rsquo;s effects on CRF, body composition, and biochemical levels and 2) to determine changes in the functional outcome, overall disease severity, and quality of life of participants.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy design, ethical approval, and registration\\u003c/h2\\u003e \\u003cp\\u003eThe TRACE-RMD study will be a randomized, single-blind (\\u003cem\\u003ei.e.\\u003c/em\\u003e, medical specialists will evaluate the psychiatric variables) controlled experimental trial. The study protocol was written per the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines(\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e) and the updated SPIRIT 2024 and CONSORT 2024 reporting guidelines (\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e), aiming to improve the quality of the intended clinical trial.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eParticipants: Recruitment and selection criteria\\u003c/h2\\u003e \\u003cp\\u003e Specialized psychiatrists from the Resistant Depression Unit of the \\u0026Aacute;lava Psychiatric Hospital and \\u0026Aacute;lava Mental Health Network (Basque Country, Spain) will recruit 70 adults with RMD, which provides psychiatric care to the population living in the community and encourage participation by explaining the benefits of exercise as an adjuvant programme in their treatment. The inclusion and exclusion criteria for the TRACE-RMD study are shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eInclusion and exclusion criteria for the TRACE-RMD study.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"1\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eInclusion criteria\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e- \\u0026ge;\\u0026thinsp;18 years old.\\u003c/p\\u003e \\u003cp\\u003e- Patients living in the community or hospitalized patients. In the two cases, the RMD diagnosis is defined as the person who receives the treatment does not have a remission, with a poor or unsatisfactory response to at least two adequate (i.e., optimal dosage and duration) different antidepressants. However, previous research studies have demonstrated the lack of consensus criteria in defining RMD.(6)\\u003c/p\\u003e \\u003cp\\u003e- Treatment-resistant depression is defined as resistance to two or more antidepressants.\\u003c/p\\u003e \\u003cp\\u003e- Written informed consent has been signed.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eExclusion criteria\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e- Schizophrenia or other psychoses.\\u003c/p\\u003e \\u003cp\\u003e- Presence of imminent suicidal risk.\\u003c/p\\u003e \\u003cp\\u003e- Unstable or inadequately controlled medical illnesses (in acute pathology situations).\\u003c/p\\u003e \\u003cp\\u003e- Active substance use disorder.\\u003c/p\\u003e \\u003cp\\u003e- Comorbidity with other psychiatric pathologies constitutes the main focus of treatment.\\u003c/p\\u003e \\u003cp\\u003e- Cognitive impairment anchored by the Montreal Cognitive Assessment scale\\u0026thinsp;\\u0026lt;\\u0026thinsp;26/30.\\u003c/p\\u003e \\u003cp\\u003e- Inability to perform exercise secondary to osteoarticular, cardiovascular or metabolic difficulties.\\u003c/p\\u003e \\u003cp\\u003e- Performing exercise continuously as a regular practice.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"1\\\"\\u003e\\u0026ge;, greater than or equal to; RMD: Resistant mayor depression.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eParticipants will be free to withdraw from the study at any time. The participant may not continue in the study for the following reasons: 1) failure to maintain 80% compliance with training sessions (minimum 19 sessions); 2) missing more than two consecutive training sessions; 3) the participant's condition or disease progresses; 4) the participant experiences a severe adverse event (\\u003cem\\u003ee.g.\\u003c/em\\u003e, angina, dyspnoea, dizziness) that requires discontinuation or withdrawal from the study in accordance with the study protocol; or 5) pregnancy.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eRandomization\\u003c/h2\\u003e \\u003cp\\u003eAfter the informed consent is accepted and signed, the participants will be included in the trial by being given a trial-specific anonymous identification (\\u003cem\\u003ei.e.\\u003c/em\\u003e, TRACE-01) number (ID). Allocation consignment will be performed by a technician from Bioaraba Research Institute (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttp://aleatorizacion.bioaraba.org/\\u003c/span\\u003e\\u003cspan address=\\\"http://aleatorizacion.bioaraba.org/\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e) using the technique of stratified randomization (1:1) by sex (men/women) and depressive symptoms. The participants will be randomized to one of the two intervention groups: 1) the exercise (EX) group and 2) the TAU group. Exercise physiologists will be responsible for informing each participant of the group in which they will participate. Figure\\u0026nbsp;1 presents a flow diagram of the study process.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eOutcomes and measurements\\u003c/h2\\u003e \\u003cp\\u003eData collection will be based on an assessment protocol for gathering data on physical, clinical, and biochemical variables. Assessments used in the protocol will be evaluated before (T0) and after a 12-week intervention period (T1). Participants from the two groups will be assessed concurrently. Sociodemographic data (including participant sex, age, state of convivence, professional status, drug and smoking status, age of onset of illness, number of hospitalizations, date of last hospitalization, medication intake, and treatment duration) will be collected before the baseline assessment. Measurements will be performed in three separate visits according to the sequence:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003eVisit 1: functional outcome and quality of life with questionnaires.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eVisit 2: anthropometry, body composition and cardiopulmonary exercise test (CPET).\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eVisit 3: fasting blood sample\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe primary outcome (depressive symptoms) will be measured with the Montgomery-Asberg Depression Rating Scale (MADRS) using the validated Spanish version (\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e). Secondary outcome variables will include CRF, body composition, biochemical and functional outcomes, and quality of life. The SPIRIT figure showing the time points for assessments and intervention is shown in Fig.\\u0026nbsp;2.\\u003c/p\\u003e \\u003cp\\u003eThe MADRS is a clinical interview with extended phrased questions about symptoms of depression and anxiety. The questionnaire has 10 different items about depression. Adding up scores can be obtained between 0 (zero; absence of depression) and 60 (major level of depression) (\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eFor evaluating functionality, the Sheehan Disability Scale (SDS)(\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e) and the Spanish version of the Quality of Life in Depression Scale (QLDS) (\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e) will be used. The copyright license agreement for the SDS was obtained through Dr. David V. Sheehan, and it included a Spanish linguistic validation. The SDS is a subjective scale with three items (social, family, and work) evaluating the incapacity o depression (\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e), and the QLDS is a depression-specific quality of life scale based on the possibility and capacity of the individual to satisfy the particular needs (\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e). The overall disease severity will be measured using the Clinical Global Impression Scale \\u0026ndash; Severity of Illness (CGI-SI). The CGI-SI is a descriptive, hetero-applied scale that provides qualitative information on the severity of the clinical condition and the change experienced by the patient concerning the baseline condition in three different measures (\\u003cem\\u003ei.e.\\u003c/em\\u003e, illness severity, global improvement, and efficacy index) (\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eAnthropometry will include stature (SECA 213, Hamburg, Germany), total body mass (SECA 869, Hamburg, Germany) BMI calculated as total body mass (kg)/stature (m\\u003csup\\u003e2\\u003c/sup\\u003e), and waist and hip circumferences calculated with waist-to-hip ratio (SECA 200, Hamburg, Germany). All measurements will follow the International Society for the Advancement of Kinanthropometry guidelines (\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e). Furthermore, bioelectrical impedance analysis will estimate fat-free mass, total body water, and fat mass (Tanita, BF 350, and Tanita, BC-418 MA, Amsterdam, the Netherlands).\\u003c/p\\u003e \\u003cp\\u003eThe International Physical Activity Questionnaire (IPAQ) will assess physical activity level and sedentary behaviour. This questionnaire has seven items, and the participant should respond on their ownbase over the prior seven days (\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e). The Spanish version of the Short Form \\u0026ndash; 36 Health Survey (SF-36) will assess participants\\u0026rsquo; health-related quality of life. The SF-36 is a short questionnaire with 36 items of eight dimensions of items, including physical functioning, social functioning, role limitations attributed to physical problems, role limitations attributed to emotional problems, mental health, vitality, pain, and general health perception (\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eThe CRF assessment will involve a symptom-limited CPET on a bike ergometer (Lode Excalibur, Groningen, the Netherlands). The protocol will commence at 40 W, with gradual increments of 10 W per min until exhaustion while continuously monitoring an electrocardiogram. The gas analyser (Ergo CardMedi-soft S.S, Belgium Ref. USM001 V1.0) will undergo calibration before each test. Peak oxygen uptake (VO\\u003csub\\u003e2peak\\u003c/sub\\u003e) will be defined as the highest oxygen consumption value achieved after the test. Peak effort will be acknowledged when meeting at least two or more of the following criteria: participant fatigue (Borg scale\\u0026thinsp;\\u0026gt;\\u0026thinsp;18), respiratory exchange\\u0026thinsp;\\u0026ge;\\u0026thinsp;1.1, attainment of \\u0026gt;\\u0026thinsp;85% of predicted maximum heart rate (HR), and no increase in VO\\u003csub\\u003e2\\u003c/sub\\u003e and/or HR with escalating workload (\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eAfter each minute, the subjective sensation of exertion will be documented using the original Borg scale (\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e). Blood pressure (BP) will be assessed at two-minute intervals throughout the test. Ventilatory thresholds (VTs) will be evaluated through standardized methodologies employing V-slope and ventilatory equivalents (EqV). The first ventilatory threshold (VT\\u003csub\\u003e1\\u003c/sub\\u003e) will be determined when the inflection point in the carbon dioxide production (VCO2) \\u003cem\\u003eversus\\u003c/em\\u003e VO2 slope transitions from less than 1 to greater than 1. Alternatively, it can be identified as the nadir in the EqV ratio of VO\\u003csub\\u003e2\\u003c/sub\\u003e \\u003cem\\u003eversus\\u003c/em\\u003e workload. The second ventilatory threshold (VT\\u003csub\\u003e2\\u003c/sub\\u003e) will be pinpointed as the nadir in the EqV/VCO\\u003csub\\u003e2\\u003c/sub\\u003e ratio \\u003cem\\u003eversus\\u003c/em\\u003e workload (\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e). After completing the test, the participant will remain at rest on the bicycle for an additional 5 min to record recovery variables. All absolute and relative criteria for concluding the test will be duly considered. The intensity ranges will be individually tailored based on HR to establish light (ranging from a resting HR value to an HR value of the VT\\u003csub\\u003e1\\u003c/sub\\u003e) and moderate (HR value between VT\\u003csub\\u003e1\\u003c/sub\\u003e and VT\\u003csub\\u003e2\\u003c/sub\\u003e) intensity categories: specifically, R1 \\u0026ndash; light to moderate intensity with HR values below VT\\u003csub\\u003e1\\u003c/sub\\u003e; R2 \\u0026ndash; moderate-to-high intensity with HR values between VT\\u003csub\\u003e1\\u003c/sub\\u003e and VT\\u003csub\\u003e2\\u003c/sub\\u003e; and R3 \\u0026ndash; intense-to-severe intensity with HR values above VT\\u003csub\\u003e2\\u003c/sub\\u003e up to peak HR.\\u003c/p\\u003e \\u003cp\\u003eBiochemical profiles will be determined with a fasting blood sample (10 mL) collected at the hospital for each participant after an overnight fast, including the following parameters: haemoglobin, haematocrit, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, C-reactive protein, uric acid, creatinine, sodium, potassium, and albumin. HOMA-IR will be used to evaluate insulin resistance (\\u003cem\\u003ei.e.\\u003c/em\\u003e, fasting serum insulin [\\u0026micro;U/mL] \\u0026times; fasting plasma glucose [mg/dL] / 405) (\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e). Moreover, cytokine levels in IL-1, IL-6, and IL-10 plasma levels will be measured via enzyme immunoassays.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy intervention\\u003c/h2\\u003e \\u003cp\\u003eThe participants enrolled in the EX group will undergo a 12-week exercise program (two non-consecutive days per week) under the supervision of exercise specialists at out-of-hospital facilities (\\u003cem\\u003ei.e.\\u003c/em\\u003e, the Physical Activity for Health Research Center). All sessions will start and end with BP measurements, and exercise intensity will be monitored by HR monitors (Polar Electro, Kempele, Finland) and through the original Borg scale (\\u003cspan additionalcitationids=\\\"CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\\\" citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e). Each session will include a 10 min warm-up and a 10 min cool-down with stretching. The main part of the session will consist of a four-part circuit of 10 min each: 1) a low-volume and low-intensity interval training (LV-LIIT) exercise on the bicycle (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e); 2) strength-resistance exercises (elastic bands, own body weight, dumbbells [Additional file 1]); 3) an LV-LIIT exercise on the bicycle (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e); and 4) lumbopelvic strengthening exercises (Additional file 1). During the sessions, the power and speed of the bike will be adjusted to achieve the target HR. In the LV-LIIT exercise, participants will warm up for 2 min and then engage in six intervals of 15 s at R2 interspersed with 1-min intervals at R1, finishing with 2 min of cool-down at R1 (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). In the resistance workout, the participants will perform a time-based circuit (30 s per exercise, with 30 s rest) of 10 strength-resistance exercises, including both upper and lower body, covering the main muscle groups and coordinated with breathing. In the lumbopelvic strengthening workout, the participants will carry out six exercises (20 repetitions with 20 s of rest between each exercise), including the anterior and posterior musculature (Additional file 1). Some strategies will be used to achieve adherence, such as individualized attention while exercising and telephone calls following missed sessions. The TAU group will conduct a standard practice and continue with their regular treatment plus occupational activities (inpatient) for the same duration as the intervention in the EX group. Due to RMD, it is not necessary to instruct participants not to engage in any other activity involving exercise because the difficulty involves them in the project. To promote retention in the project, after completion of the post-intervention assessments, all participants are offered an exercise programme within the hospital (unrelated to the research).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eExercise intervention through low-intensity interval training on a cycle ergometer\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"6\\\" nameend=\\\"c6\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eProtocol\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c3\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eModerate-intensity interval training\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c6\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eLow-intensity interval training\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eWeeks\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eVolume (min)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eIntensity (%HR\\u003c/b\\u003e\\u003csub\\u003e\\u003cb\\u003eres\\u003c/b\\u003e\\u003c/sub\\u003e\\u003cb\\u003e)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eWeeks\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eVolume (min)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eIntensity (%HR\\u003c/b\\u003e\\u003csub\\u003e\\u003cb\\u003eres\\u003c/b\\u003e\\u003c/sub\\u003e\\u003cb\\u003e)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e1\\u0026ndash;4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e60\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1\\u0026ndash;4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e50\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e5\\u0026ndash;8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e65\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e5\\u0026ndash;8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e55\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e9\\u0026ndash;12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e70\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e9\\u0026ndash;12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e60\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eIn case of adverse events will be recorded and reported to the corresponding Ethics Committee.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eData management\\u003c/h2\\u003e \\u003cp\\u003eAll data recording will be carried out by the lead research psychiatrist (NIY) and the persons responsible for the exercise programme (JEO \\u0026amp; MTE). The database shall be coded, and only the persons responsible for the research will have access to it.\\u003c/p\\u003e \\u003cp\\u003eUpon completion of the study, the results will be published and presented to social media, academics, and clinical institutions. Likewise, research articles will be submitted to peer-reviewed journals and presented at relevant scientific conferences.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec9\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eSample size estimation\\u003c/h2\\u003e \\u003cp\\u003eBased on a previous pilot study with the same population, to achieve a power of 80% where differences in depressive symptoms (measured by the MADRS) are detected after the exercise intervention, having a significance of 5%, a reference mean of 29.13\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;12.2 units, an experimental group mean of 22.23 units, a standard deviation between both groups of 9.61, and an expected difference of 2.5 units, 31 patients per group will be needed. If we assume a 10% loss rate, 35 patients per group will be required, with a total sample of 70 participants.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eA general descriptive analysis of the sample will be performed to assess baseline homogeneity. The Kolmogorov-Smirnov test will determine the normality of quantitative variables, and results will be expressed as means and standard deviations or as median values and interquartile ranges in the case of non-normal distributions. Qualitative variables will be expressed as frequencies and percentages. Student\\u0026rsquo;s \\u003cem\\u003et\\u003c/em\\u003e-test for related samples will be carried out to assess the impact of the intervention on quantitative variables. A nonparametric analog Wilcoxon will be chosen if it does not meet normality criteria. A covariate analysis (ANCOVA) will evaluate change after the intervention, considering the two EX and TAU groups (\\u003cem\\u003ei.e.\\u003c/em\\u003e, independent variable). The magnitude of the differences will be assessed using 95% confidence intervals and Hedges's \\u003cem\\u003eg\\u003c/em\\u003e effect sizes.\\u003c/p\\u003e \\u003cp\\u003eDuring the development of the study, deviations from the protocol may arise. The statistical analysis will be performed via intention-to-treat and protocol to manage these situations within the study.\\u003c/p\\u003e \\u003cp\\u003eThe TRACE-RMD study does not have a data monitoring committee, and the Ethical Committee does not require it, given the project is under constant review of the psychiatry specialists.\\u003c/p\\u003e \\u003cp\\u003eNo interim analyses are planned.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eThis study will be the first clinical trial to explore the efficacy of a combined exercise intervention as a potential co-adjuvant to pharmacological treatment in patients with an RMD diagnosis. Recent meta-analyses have shown that different types and dose-responses of exercises like walking, aerobic training, Yoga, Qigong, resistance training, and Tai Chi have effectively alleviated depressive symptoms in older adults (\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e), and adults in general (\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e). Therefore, since RMD populations can be resistant to two or more antidepressants (\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e), exercise interventions should be considered an effective adjuvant program in the treatment of RMD.\\u003c/p\\u003e \\u003cp\\u003eIn this sense, the appropriate FITT principle of exercise interventions remains unclear, and controversy exists (\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e). Moreover, although a significant percentage of interventions are aerobically oriented, a recent meta-analysis revealed moderate antidepressant effects of strength training in people with a diagnosis of depression or depressive symptoms (\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e). Therefore, combined training (\\u003cem\\u003ei.e.\\u003c/em\\u003e, aerobic + resistance training in the same session) could be considered a powerful option to investigate in people with RMD. Thus, previous studies have implemented and analysed exercise interventions in people with RMD (\\u003cspan additionalcitationids=\\\"CR11\\\" citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e–\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e). While these interventions have shown improvements in psychiatric variables, enhancing psychopathological symptoms like depression, functionality, and even quality of life, none has implemented a combined exercise training intervention or analysed potential physical, objective physiological, and biochemical improvements in this population. In this regard, given that the improvement in CRF through exercise training has led to enhanced health and reduced mortality in people with severe mental illness (\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e), to analyse this variable is crucial.\\u003c/p\\u003e \\u003cp\\u003eFurthermore, the biochemical analysis will provide the opportunity to examine IL-6 and IL-1, which have been associated with the onset of proinflammatory inflammation and are particularly relevant in the brain (\\u003cspan additionalcitationids=\\\"CR37\\\" citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e–\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e). In line with this, peripheral cytokines can cross the blood-brain barrier and reach the central nervous system, provoking neuroinflammation, which might trigger psychiatric disorders such as depression (\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e). Therefore, analysing these ILs will be pertinent, as exercise interventions have been shown to decrease IL-6 levels (\\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e). Overall, this research will provide further information and build upon previous findings regarding a co-adjunctive strategy (combined exercise training) in individuals diagnosed with RMD.\\u003c/p\\u003e \"},{\"header\":\"Trial Status\",\"content\":\"\\u003cp\\u003eThe trial was initially released as a pilot study (no clinical trial) on 24th November 2021 (version 1). The present manuscript is based on the 18th December 2023 trial protocol (version 2). Recruitment of participants started in January 2024 and is estimated to be completed up to December 2025.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cdiv class=\\\"DefinitionList\\\"\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eBMI\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eBody Mass Index\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eBP\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eBlood Pressure\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eCGI-SI\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eClinical Global Impression Scale-Severity of Illness\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eCPET\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eCardioPulmonary Exercise Test\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eCRF\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eCardioRespiratory Fitness\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eEqV\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eVentilatory Equivalent\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eEX\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eexercise\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eFITT\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eFrequency, Intensity, Time and Type\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eHR\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eHeart Rate\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eIL\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eInterLeukin\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eIPAQ\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eInternational Physical Activity Questionnaire\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eLV-LIIT\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eLow-Volume and Low-Intensity Interval Training\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eMADRS\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eMontgomery-Asberg Depression Rating Scale\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eMDD\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eMajor Depressive Disorder\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eQLDS\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eQuality of Life in Depression Scale\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eRMD\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eResistant Major Depression\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eSDS\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eSheehan Disability Scale\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eSF-36\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eShort Form-36 Health Survey\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTAU\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eTreatment As Usual\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eVCO\\u003csub\\u003e2\\u003c/sub\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eCarbon Dioxide Production\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eVO\\u003csub\\u003e2peak\\u003c/sub\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003ePeak Oxygen Uptake\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eVT\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eVentilatory Threshold\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003c/div\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe design of the study conforms to the principles outlined in the Declaration of Helsinki, and the protocol, together with the informed consent procedures of the TRACE-RMD study, were approved by the Ethics Committee of Investigation of the local Hospital (11 May 2023, Certificate No. 2023-008). The protocol was registered with the United States National Library of Medicine (Clinical Trials.gov ID no. NCT05136027). Participants will be fully informed of the aims and procedures of the research before collecting their informed consent and before the clinical and physiological examination. Each participant\\u0026nbsp;will be allowed to ask questions about the investigation.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication.\\u0026nbsp;\\u003c/strong\\u003eNot applicable\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interest.\\u0026nbsp;\\u003c/strong\\u003eThe authors declare that they have no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis project was funded by the \\u0026quot;III Convocatoria Intramural de la Fundaci\\u0026oacute;n Vital Fundazioa \\u0026ndash; IIS BIOARABA\\u0026quot; and the Mental Health Network of \\u0026Aacute;lava.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors\\u0026rsquo; contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll authors read and approved the final manuscript. Conception of the project (NIY, JEO, CPN, MTE, PMSG, SMM, EEZ). Design of the work and methodology (NIY, JEO, CPN, MTE, PMSG, SMM, ABYE, EEZ).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data ana materials\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data will be available from the corresponding author upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThanks to the Mental Health Network of Araba for the commitment in this project, and the GIKAFIT research group at the University of the Basque Country (UPV/EHU). Likewise, thanks to IIS BIOARABA for all the methodological support and Vitoria-Gasteiz City Council for transferring the facilities for the physical activity of the health research centre.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eIgn\\u0026aacute;cio ZM, da Silva RS, Plissari ME, Quevedo J, R\\u0026eacute;us GZ. Physical Exercise and Neuroinflammation in Major Depressive Disorder. Mol Neurobiol 2019;56(12):8323\\u0026ndash;8335.\\u003c/li\\u003e\\n\\u003cli\\u003eCichon S, Craddock N, Daly M, Faraone SV, Gejman PV, Kelsoe J, et al. Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry 2009 -05;166(5):540\\u0026ndash;556.\\u003c/li\\u003e\\n\\u003cli\\u003eGuti\\u0026eacute;rrez-Rojas L, Porras-Segovia A, Dunne H, Andrade-Gonz\\u0026aacute;lez N, Cervilla JA. Prevalence and correlates of major depressive disorder: a systematic review. Revista brasileira de psiquiatria 2020 Aug 03,;42(6):657\\u0026ndash;672.\\u003c/li\\u003e\\n\\u003cli\\u003eBennabi D, Aouizerate B, El-Hage W, Doumy O, Moliere F, Courtet P, et al. Risk factors for treatment resistance in unipolar depression: A systematic review. Journal of affective disorders 2014;171:137\\u0026ndash;141.\\u003c/li\\u003e\\n\\u003cli\\u003eKurian BT, Greer TL, Trivedi MH. Strategies to enhance the therapeutic efficacy of antidepressants: targeting residual symptoms. Expert review of neurotherapeutics 2009 Jul 01,;9(7):975\\u0026ndash;984.\\u003c/li\\u003e\\n\\u003cli\\u003eHarbi KSA. Treatment-resistant depression: Therapeutic trends, challenges, and future directions. Patient preference and adherence 2012;6:369\\u0026ndash;388.\\u003c/li\\u003e\\n\\u003cli\\u003eTrivedi MH, Daly EJ. Treatment strategies to improve and sustain remission in major depressive disorder. Dialogues Clin Neurosci 2008;10(4):377\\u0026ndash;384.\\u003c/li\\u003e\\n\\u003cli\\u003eKrogh J, Hjorth\\u0026oslash;j C, Speyer H, Gluud C, Nordentoft M. Exercise for patients with major depression: a systematic review with meta-analysis and trial sequential analysis. BMJ Open 2017 -09-18;7(9):e014820.\\u003c/li\\u003e\\n\\u003cli\\u003eBull FC, Al-Ansari SS, Biddle S, Borodulin K, Buman MP, Cardon G, et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br J Sports Med 2020;54(24).\\u003c/li\\u003e\\n\\u003cli\\u003eTrivedi M, Greer TL, Blair SN, Church TS, Carmody TJ, Grannemann BD, et al. Exercise as an augmentation treatment for nonremitted major depressive disorder: a randomized, parallel dose comparison. The journal of clinical psychiatry 2011;72(5):677\\u0026ndash;684.\\u003c/li\\u003e\\n\\u003cli\\u003eMota-Pereira J, Silverio J, Carvalho S, Ribeiro JC, Fonte D, Ramos J. Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder. Journal of Psychiatric Research 2011;45(8):1005\\u0026ndash;1011.\\u003c/li\\u003e\\n\\u003cli\\u003eMather A, Rodriguez C, Guthrie M, Mcharg A, Reid I, McMurdo M. Effects of exercise on depressive symptoms in older adults with poorly responsive depressive disorder\\u003cbr\\u003e . British Journal Of Psychiatry 2002;180(411-145):1\\u0026ndash;6.\\u003c/li\\u003e\\n\\u003cli\\u003eHorv\\u0026aacute;th J, Debreceni Nagy A, F\\u0026uuml;l\\u0026ouml;p P, Jenei Z. Effectiveness of hospital-based low intensity and inspected aerobic training on functionality and cardiorespiratory fitness in unconditioned stroke patients: Importance of submaximal aerobic fitness markers. Medicine 2022 -10-21;101(42).\\u003c/li\\u003e\\n\\u003cli\\u003eL\\u0026ouml;llgen H, V\\u0026ouml;lker K, B\\u0026ouml;ckenhoff A, L\\u0026ouml;llgen D, K\\u0026ouml;rperliche B\\u0026bull;, Sterblichkeit AT\\u0026bull;, et al. K\\u0026ouml;rperliche Aktivit\\u0026auml;t und Prim\\u0026auml;rpr\\u0026auml;vention kardiovaskul\\u0026auml;rer Erkrankungen (Physical activity and prevention of cardiovascular diseases). Springer Link 2006 Sep;31(6):519\\u0026ndash;523.\\u003c/li\\u003e\\n\\u003cli\\u003eChan A, Tetzlaff JM, Altman DG, Laupacis A, G\\u0026oslash;tzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013 Feb 5;158(3):200\\u0026ndash;207.\\u003c/li\\u003e\\n\\u003cli\\u003eTunn R, Boutron I, Chan A, Collins GS, Hr\\u0026oacute;bjartsson A, Moher D, et al. Methods used to develop the SPIRIT 2024 and CONSORT 2024 Statements. J Clin Epidemiol 2024 /05/01;169.\\u003c/li\\u003e\\n\\u003cli\\u003eLobo A, Chamorro L, Luque A, Dal-R\\u0026eacute; R, Badia X, Bar\\u0026oacute; E. Validaci\\u0026oacute;n de las versiones en espa\\u0026ntilde;ol de la Montgomery-Asberg Depression Rating Scale y la Hamilton Anxiety Rating Scale para la evaluaci\\u0026oacute;n de la depresi\\u0026oacute;n y de la ansiedad ([Validation of the Spanish versions of the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale for the assessment of depression and anxiety]). Medicina Cl\\u0026iacute;nica 2002;118(13):493\\u0026ndash;499.\\u003c/li\\u003e\\n\\u003cli\\u003eSheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol 1996 Jun;11 Suppl 3:89\\u0026ndash;95.\\u003c/li\\u003e\\n\\u003cli\\u003eCervera-Enguix S, Ram\\u0026iacute;rez N, Girala N, McKenna SP. The development and validation of a Spanish version of the quality of life in depression scale (QLDS). Eur Psychiatry 1999 Nov;14(7):392\\u0026ndash;398.\\u003c/li\\u003e\\n\\u003cli\\u003eBabes J, Bad\\u0026iacute;a X, Luque A, Garcia M, Gonzalez MP, Dal-R\\u0026eacute; R. Validaci\\u0026oacute;n de las versiones en espa\\u0026ntilde;ol de los cuestionarios Liebowitz Social Anxiety Scale, Social Anxiety and Distress Scale y Sheehan Disability Inventory para la evaluaci\\u0026oacute;n de la fobia social. . Med Clin (Barc) 1999.\\u003c/li\\u003e\\n\\u003cli\\u003eGuy W, National Institute of Mental Health (US) Psychopharmacology, Research Branch, Early Clinical Drug EP. ECDEU assessment manual for psychopharmacology. Rev ed. Rockville, Md.: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976.\\u003c/li\\u003e\\n\\u003cli\\u003eKadouri A, Corruble E, Falissard B. The improved Clinical Global Impression Scale (iCGI): development and validation in depression. BMC Psychiatry 2007 -02-06;7(1).\\u003c/li\\u003e\\n\\u003cli\\u003eNorton K. Measurement techniques in anthropometry. Antropometrica 1996.\\u003c/li\\u003e\\n\\u003cli\\u003eRoman-Vi\\u0026ntilde;as B, Serra-Majem L, Hagstr\\u0026ouml;mer M, Ribas-Barba L, Sj\\u0026ouml;str\\u0026ouml;m M, Segura-Cardona R. International Physical Activity Questionnaire: Reliability and validity in a Spanish population. European journal of sport science 2010 Sep 01,;10(5):297\\u0026ndash;304.\\u003c/li\\u003e\\n\\u003cli\\u003eAyuso-Mateos JL, Lasa L, V\\u0026aacute;zquez-Barquero JL, Oviedo A, Diez-Manrique JF. Measuring health status in psychiatric community surveys: internal and external validity of the Spanish version of the SF-36. Acta psychiatrica Scandinavica 1999 Jan;99(1):26\\u0026ndash;32.\\u003c/li\\u003e\\n\\u003cli\\u003eMezzani A, Hamm LF, Jones AM, McBride PE, Moholdt T, Stone JA, et al. Aerobic exercise intensity assessment and prescription in cardiac rehabilitation: a joint position statement of the European Association for Cardiovascular Prevention and Rehabilitation, the American Association of Cardiovascular and Pulmonary Rehabilitation and the Canadian Association of Cardiac Rehabilitation. European journal of preventive cardiology 2013 Jun;20(3):442\\u0026ndash;467.\\u003c/li\\u003e\\n\\u003cli\\u003eBorg G. Borg\\u0026acute;s Perceived Exertion and Pain Scales. Champaingn, IL: Human Kinetics 1998.\\u003c/li\\u003e\\n\\u003cli\\u003eMatthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and -cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985 Jul;28(7):412\\u0026ndash;419.\\u003c/li\\u003e\\n\\u003cli\\u003eTang L, Zhang L, Liu Y, Li Y, Yang L, Zou M, et al. Optimal dose and type of exercise to improve depressive symptoms in older adults: a systematic review and network meta-analysis. BMC Geriatr 2024 Jun 7;24(1):505\\u0026ndash;7.\\u003c/li\\u003e\\n\\u003cli\\u003eNoetel M, Sanders T, Gallardo-G\\u0026oacute;mez D, Taylor P, Del Pozo Cruz B, van den Hoek D, et al. Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials. BMJ 2024 Feb 14;384:e075847\\u0026ndash;075847.\\u003c/li\\u003e\\n\\u003cli\\u003eContreras-Osorio F, Ramirez-Campillo R, Cerda-Vega E, Campos-Jara R, Mart\\u0026iacute;nez-Salazar C, Reigal RE, et al. Effects of Physical Exercise on Executive Function in Adults with Depression: A Systematic Review and Meta-Analysis. IJERPH 2022 -11-18;19(22).\\u003c/li\\u003e\\n\\u003cli\\u003eRosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB. Physical activity interventions for people with mental illness: a systematic review and meta-analysis. J Clin Psychiatry 2014 Sep;75(9):964\\u0026ndash;974.\\u003c/li\\u003e\\n\\u003cli\\u003eRossi FE, Dos Santos GG, Rossi PAQ, Stubbs B, Barreto Schuch F, Neves LM. Strength training has antidepressant effects in people with depression or depressive symptoms but no other severe diseases: A systematic review with meta-analysis. Psychiatry Res 2024 Apr;334:115805.\\u003c/li\\u003e\\n\\u003cli\\u003eCarta MG, Hardoy MC, Pilu A, Sorba M, Floris AL, Mannu FA, et al. Improving physical quality of life with group physical activity in the adjunctive treatment of major depressive disorder. Clin Pract Epidemiol Ment Health 2008 Jan 26;4:1\\u0026ndash;1.\\u003c/li\\u003e\\n\\u003cli\\u003eVancampfort D, Rosenbaum S, Schuch F, Ward PB, Richards J, Mugisha J, et al. Cardiorespiratory Fitness in Severe Mental Illness: A Systematic Review and Meta-analysis. Sports Med 2017 Feb;47(2):343\\u0026ndash;352.\\u003c/li\\u003e\\n\\u003cli\\u003eTing EY, Yang AC, Tsai S. Role of Interleukin-6 in Depressive Disorder. IJMS 2020 -03-22;21(6).\\u003c/li\\u003e\\n\\u003cli\\u003eLicinio J, Wong ML. The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999 Jul;4(4):317\\u0026ndash;327.\\u003c/li\\u003e\\n\\u003cli\\u003eDantzer R, Wollman E, Vitkovic L, Yirmiya R. Cytokines and depression: fortuitous or causative association? Mol Psychiatry 1999 Jul;4(4):328\\u0026ndash;332.\\u003c/li\\u003e\\n\\u003cli\\u003eR\\u0026eacute;us GZ, Manosso LM, Quevedo J, Carvalho AF. Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities. Neurosci Biobehav Rev 2023 Dec;155:105425.\\u003c/li\\u003e\\n\\u003cli\\u003eLeg\\u0026aring;rd GE, Pedersen BK. Chapter 13 - Muscle as an Endocrine Organ. In: Zoladz JA, editor. Muscle and Exercise Physiology: Academic Press; 2019. p. 285\\u0026ndash;307.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"trials\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"trls\",\"sideBox\":\"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)\",\"snPcode\":\"13063\",\"submissionUrl\":\"https://www.editorialmanager.com/trls\",\"title\":\"Trials\",\"twitterHandle\":\"MedicalEvidence\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC/SO AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Resistant Major Depression, exercise, quality of life, combined training\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4946519/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4946519/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eAround 40% of people with major depressive disorder (MDD) experience moderate remission, with the remainder meeting the criteria for resistant major depression (RMD). It has been shown that exercise has a low-to-moderate effect on MDD, but there is a lack of evidence on exercise interventions in RMD patients. The primary purpose of the proposed study will be to investigate the effect of a 12-week supervised combined exercise program on depressive symptoms in people with RMD compared to a treatment-as-usual (TAU) group.\\u003c/p\\u003e\\u003ch2\\u003eMethod\\u003c/h2\\u003e \\u003cp\\u003eThis randomized, single-blind, controlled experimental trial will include 70 adults (\\u0026ge;\\u0026thinsp;18 years old) with RMD. Participants randomized to an exercise intervention or a TAU group will be assessed at baseline and after a three-month intervention period. The primary variable will be participants\\u0026rsquo; depressive symptoms measured with the Montgomery-Asberg Depression Rating Scale. Secondary outcome variables will include cardiorespiratory fitness (peak oxygen uptake through peak cardiopulmonary exercise test), body composition (bioimpedance and anthropometric variables), physical activity level (the International Physical Activity Questionnaire), health-related quality of life (the Short Form \\u0026ndash; 36 Health Survey), functional outcome (the Sheehan Disability Scale and Quality of Life in Depression Scale), overall disease severity (the Clinical Global Impression Scale \\u0026ndash; Severity of Illness), and biochemical variables (a fasting blood sample).\\u003c/p\\u003e\\u003ch2\\u003eDiscussion\\u003c/h2\\u003e \\u003cp\\u003eThis study will try to answer whether a supervised co-adjuvant combined (aerobic and resistance training) exercise program will help the prognosis of this population with RMD.\\u003c/p\\u003e\\u003ch2\\u003eTrial registration\\u003c/h2\\u003e \\u003cp\\u003eClinicalTrials.gov, identifier NCT05136027. 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