PreprintPDF Available

Treatment with combined exercise in patients with resistant major depression (TRACE-RMD): study protocol for a randomized clinical trial

Authors:

Abstract and Figures

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
Content may be subject to copyright.
Page 1/18
Treatment with combined exercise in patients with
resistant major depression (TRACE-RMD): study
protocol for a randomized clinical trial
Nagore Iriarte-Yoller
Osakidetza Basque Health Service. Araba Mental Health Network
Jose Echaniz-Oses
UNIVERSITY OF THE BASQUE COUNTRY (UPV/EHU)
Cristobal Pavón-Navajas
Osakidetza Basque Health Service. Araba Mental Health Network
Mikel Tous-Espelosin
UNIVERSITY OF THE BASQUE COUNTRY (UPV/EHU)
Pedro M. Sánchez-Gómez
Osakidetza Basque Health Service. Bizkaia Mental Health Network
SARA MALDONADO-MARTIN
UNIVERSITY OF THE BASQUE COUNTRY https://orcid.org/0000-0002-2622-5385
Ana B. Yoller-Elburgo
Osakidetza Basque Health Service. Araba Mental Health Network
Edorta Elizagarate-Zabala
Osakidetza Basque Health Service. Araba Mental Health Network
Research Article
Keywords: Resistant Major Depression, exercise, quality of life, combined training
Posted Date: December 2nd, 2024
DOI: https://doi.org/10.21203/rs.3.rs-4946519/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License. 
Read Full License
Page 2/18
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 tness (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, identier NCT05136027. Last public release on 12/13/2023
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
inammation (1, 2).
Page 3/18
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 proinammatory 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 insucient. 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 rst- 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 dened 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 scientic 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
ecient method to improve different outcomes like cardiorespiratory tness (CRF) and body mass index
(BMI) in adult populations with chronic diseases, especially for individuals with a low initial level of
aerobic tness (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
Page 4/18
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
benets of exercise as an adjuvant programme in their treatment. The inclusion and exclusion criteria for
the TRACE-RMD study are shown in Table1.
Page 5/18
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
dened 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 dening RMD.(6)
- Treatment-resistant depression is dened 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 diculties.
- 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-specic anonymous identication (
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 stratied 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 ow diagram of the study process.
Page 6/18
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
gure 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-specic 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 ecacy 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 (m2), 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).
Page 7/18
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 (VO2peak) will be dened 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 VO2 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 rst ventilatory threshold (VT1) will be determined when the inection
point in the carbon dioxide production (VCO2)
versus
VO2 slope transitions from less than 1 to greater
than 1. Alternatively, it can be identied as the nadir in the EqV ratio of VO2
versus
workload. The second
ventilatory threshold (VT2) will be pinpointed as the nadir in the EqV/VCO2 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 VT1) and moderate (HR value between VT1 and VT2) intensity categories:
specically, R1 – light to moderate intensity with HR values below VT1; R2 – moderate-to-high intensity
with HR values between VT1 and VT2; and R3 – intense-to-severe intensity with HR values above VT2 up
to peak HR.
Biochemical proles 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
Page 8/18
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 le 1]); 3) an LV-LIIT exercise on the bicycle
(Table2); and 4) lumbopelvic strengthening exercises (Additional le 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,
nishing 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 le 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 diculty 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 (%HRres) Weeks Volume (min) Intensity (%HRres)
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
Page 9/18
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 scientic 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
signicance 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% condence 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 rst clinical trial to explore the ecacy 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.
Page 10/18
In this sense, the appropriate FITT principle of exercise interventions remains unclear, and controversy
exists (31, 32). Moreover, although a signicant 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 proinammatory inammation 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 neuroinammation, 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 ndings 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
Page 11/18
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
VCO2
Carbon Dioxide Production
VO2peak
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
Page 12/18
Ethics Committee of Investigation of the local Hospital (11 May 2023, Certicate 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 nal 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.
Acknowledgments
Thanks 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.
References
1. Ignácio ZM, da Silva RS, Plissari ME, Quevedo J, Réus GZ. Physical Exercise and Neuroinammation
in Major Depressive Disorder. Mol Neurobiol 2019;56(12):8323–8335.
2. Cichon 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):540–556.
3. Gutiérrez-Rojas L, Porras-Segovia A, Dunne H, Andrade-González N, Cervilla JA. Prevalence and
correlates of major depressive disorder: a systematic review. Revista brasileira de psiquiatria 2020
Aug 03,;42(6):657–672.
4. Bennabi 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
Page 13/18
2014;171:137–141.
5. Kurian BT, Greer TL, Trivedi MH. Strategies to enhance the therapeutic ecacy of antidepressants:
targeting residual symptoms. Expert review of neurotherapeutics 2009 Jul 01,;9(7):975–984.
. Harbi KSA. Treatment-resistant depression: Therapeutic trends, challenges, and future directions.
Patient preference and adherence 2012;6:369–388.
7. Trivedi MH, Daly EJ. Treatment strategies to improve and sustain remission in major depressive
disorder. Dialogues Clin Neurosci 2008;10(4):377–384.
. Krogh J, Hjorthøj 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.
9. Bull 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).
10. Trivedi 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):677–684.
11. Mota-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):1005–1011.
12. Mather 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
. British Journal Of Psychiatry 2002;180(411-145):1–6.
13. Horváth J, Debreceni Nagy A, Fülöp P, Jenei Z. Effectiveness of hospital-based low intensity and
inspected aerobic training on functionality and cardiorespiratory tness in unconditioned stroke
patients: Importance of submaximal aerobic tness markers. Medicine 2022 -10-21;101(42).
14. Löllgen H, Völker K, Böckenhoff A, Löllgen D, Körperliche B•, Sterblichkeit AT•, et al. Körperliche
Aktivität und Primärprävention kardiovaskulärer Erkrankungen (Physical activity and prevention of
cardiovascular diseases). Springer Link 2006 Sep;31(6):519–523.
15. Chan A, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013
statement: dening standard protocol items for clinical trials. Ann Intern Med 2013 Feb
5;158(3):200–207.
1. Tunn R, Boutron I, Chan A, Collins GS, Hróbjartsson A, Moher D, et al. Methods used to develop the
SPIRIT 2024 and CONSORT 2024 Statements. J Clin Epidemiol 2024 /05/01;169.
17. Lobo A, Chamorro L, Luque A, Dal-Ré R, Badia X, Baró E. Validación de las versiones en español de la
Montgomery-Asberg Depression Rating Scale y la Hamilton Anxiety Rating Scale para la evaluación
de la depresión 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 Clínica 2002;118(13):493–499.
Page 14/18
1. Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol
1996 Jun;11 Suppl 3:89–95.
19. Cervera-Enguix S, Ramírez 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):392–398.
20. Babes J, Badía X, Luque A, Garcia M, Gonzalez MP, Dal-Ré R. Validación de las versiones en español
de los cuestionarios Liebowitz Social Anxiety Scale, Social Anxiety and Distress Scale y Sheehan
Disability Inventory para la evaluación de la fobia social. . Med Clin (Barc) 1999.
21. Guy 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.
22. Kadouri A, Corruble E, Falissard B. The improved Clinical Global Impression Scale (iCGI):
development and validation in depression. BMC Psychiatry 2007 -02-06;7(1).
23. Norton K. Measurement techniques in anthropometry. Antropometrica 1996.
24. Roman-Viñas B, Serra-Majem L, Hagströmer M, Ribas-Barba L, Sjöström 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):297–304.
25. Ayuso-Mateos JL, Lasa L, Vázquez-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):26–32.
2. Mezzani 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):442–467.
27. Borg G. Borg´s Perceived Exertion and Pain Scales. Champaingn, IL: Human Kinetics 1998.
2. Matthews 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):412–419.
29. 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.
30. 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.
31. 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
Page 15/18
Review and Meta-Analysis. IJERPH 2022 -11-18;19(22).
32. 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.
33. Rossi 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.
34. Carta 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;4:1–1.
35. Vancampfort 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):343–352.
3. Ting EY, Yang AC, Tsai S. Role of Interleukin-6 in Depressive Disorder. IJMS 2020 -03-22;21(6).
37. Licinio J, Wong ML. The role of inammatory 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.
3. Dantzer R, Wollman E, Vitkovic L, Yirmiya R. Cytokines and depression: fortuitous or causative
association? Mol Psychiatry 1999 Jul;4(4):328–332.
39. 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.
40. 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.
Figures
Page 16/18
Figure 1
Flow diagram of the TRACE-RMD study.
Page 17/18
Figure 2
The SPIRIT gure shows an overview of the assessment schedule at baseline sand follow-up in the
TRACE-RMD study.
Supplementary Files
Page 18/18
This is a list of supplementary les associated with this preprint. Click to download.
SPIRITchecklist.docx
Additionalle1resistancetrainingprogram.pdf
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Background Depression is a prevalent issue among older adults, affecting their quality of life and overall well-being. Exercise is an effective means of relieving depressive symptoms in older adults, but the optimal dose for different exercise types remains unclear. As such, the aim of this meta-analysis was to examine the dose–response relationship between overall and specific types of exercise with depression symptoms in older adults. Methods This systematic review and network meta-analysis included a search of PubMed, Medline, Embase, PsycINFO, Cochrane library, and Web of Science for randomized controlled trials of exercise in older adults with depression symptoms from inception to 15 July 2023. Comprehensive data extraction covered dose, treatment regimen, demographics and study duration. Dosage metrics, encompassing METs-min/week, were scrutinized in correlation with the Minimal Clinically Importance Difference (MCID). Results A total of 47 studies involving 2895 participants and 7 kinds of exercise were included in the review. Without considering the dose, the results of our network meta-analysis indicated that Walking was the most effective in alleviating depression in older adults, in addition to Aerobic exercise (AE), Yoga, Qigong, Resistance training (RT), and Tai Chi (TC), which were equally effective. However, the results of the dose–response analysis found that Aerobic exercise was most effective at a dose of 1000 METs-min/week. It is noteworthy that Walking is significantly effective in alleviating depressive symptoms in older adults at very low doses. In terms of clinical benefits, we found that overall exercise doses in the range of 600 ~ 970 METs-min/week were clinically effective. Considering the specific types of exercise, Aerobic exercise, Resistance training, Walking, and Yoga were found to be effective at doses ranging from 820 ~ 1000 METs-min/week, 520 ~ 1000 METs-min/week, 650 ~ 1000 METs-min/week, 680 ~ 1000 METs-min/week, respectively. At the same time, we found that when the age exceeded 81 years, even when participating in exercise, it did not achieve the effect of alleviating depressive symptoms in older adults. Conclusions In conclusion, including Walking, AE, Yoga, Qigong, RT, and TC, effectively alleviate depressive symptoms in older adults. Furthermore, we established statistically and clinically significant threshold doses for various exercise types. Early initiation of exercise is beneficial, but its efficacy diminishes from the age of 80, and beyond 81, exercise no longer significantly alleviates depressive symptoms.
Article
Full-text available
Objective To identify the optimal dose and modality of exercise for treating major depressive disorder, compared with psychotherapy, antidepressants, and control conditions. Design Systematic review and network meta-analysis. Methods Screening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Bayesian arm based, multilevel network meta-analyses were performed for the primary analyses. Quality of the evidence for each arm was graded using the confidence in network meta-analysis (CINeMA) online tool. Data sources Cochrane Library, Medline, Embase, SPORTDiscus, and PsycINFO databases. Eligibility criteria for selecting studies Any randomised trial with exercise arms for participants meeting clinical cut-offs for major depression. Results 218 unique studies with a total of 495 arms and 14 170 participants were included. Compared with active controls (eg, usual care, placebo tablet), moderate reductions in depression were found for walking or jogging (n=1210, κ=51, Hedges’ g −0.62, 95% credible interval −0.80 to −0.45), yoga (n=1047, κ=33, g −0.55, −0.73 to −0.36), strength training (n=643, κ=22, g −0.49, −0.69 to −0.29), mixed aerobic exercises (n=1286, κ=51, g −0.43, −0.61 to −0.24), and tai chi or qigong (n=343, κ=12, g −0.42, −0.65 to −0.21). The effects of exercise were proportional to the intensity prescribed. Strength training and yoga appeared to be the most acceptable modalities. Results appeared robust to publication bias, but only one study met the Cochrane criteria for low risk of bias. As a result, confidence in accordance with CINeMA was low for walking or jogging and very low for other treatments. Conclusions Exercise is an effective treatment for depression, with walking or jogging, yoga, and strength training more effective than other exercises, particularly when intense. Yoga and strength training were well tolerated compared with other treatments. Exercise appeared equally effective for people with and without comorbidities and with different baseline levels of depression. To mitigate expectancy effects, future studies could aim to blind participants and staff. These forms of exercise could be considered alongside psychotherapy and antidepressants as core treatments for depression. Systematic review registration PROSPERO CRD42018118040.
Article
Full-text available
Executive function is among the most affected cognitive dimensions in depression. Physical ex-ercise may improve executive function (e.g., working memory, inhibition, cognitive flexibility), although without consensus on adults with depression. Through this systematic review, we aim to elucidate the effects of physical exercise programs on executive functions in adults with depression. The literature search was performed in four relevant electronic databases, combining keywords and medical subject headings, from inception until September 2022. Controlled interventions were considered includable, involving adults with depression, and reporting working memory, inhi-bition, and/or cognitive flexibility pre-post-intervention data. Meta-analyses results included effect size (ES, i.e., Hedges’ g) values reported with 95% confidence intervals (95%CIs), with p set at ≤0.05. Seven studies were included, including 202 men and 457 women (age: 21.0–51.2 years; mild–moderate depression). For working memory, a small favoring effect was observed in the ex-perimental groups compared to controls (ES = 0.33, 95%CI = 0.04–0.61; p = 0.026; I2 = 64.9%). For inhibition, physical exercise had a small favoring non-significant effect compared to controls (ES = 0.28, 95%CI = −0.17–0.74; p = 0.222; I2 = 72.4%). Compared to the control group, physical exercise had a trivial effect on cognitive flexibility (ES = 0.09, 95%CI = −0.21–0.39; p = 0.554; I2 = 68.4%). In con-clusion, physical exercise interventions may improve working memory behavioral measures in adults with mild-to-moderate depression when compared to active and passive control conditions. However, the reduced number of available high-quality studies precludes more lucid conclusions.
Article
Full-text available
Introduction: The purpose of our study was to evaluate the effectiveness of low-to moderate intensity aerobic training on cardiorespiratory functions in chronic unconditioned stroke patients. The oxygen uptake efficiency slope (OUES) and the ventilatory threshold (VO2-VT) could represent the aerobic capacity in submaximal test. Our study examined the application of the submaximal parameters for evaluating aerobic capacity of chronic stroke patients. Materials and methods: In our assessor-blinded controlled pilot study 37 patients were randomized into 2 groups named: intervention group (IG, n: 21) and control group (CG, n:16), respectively. Cardiorespiratory functions were evaluated by ergospirometer before and after the 4-week (20 days) program. Both groups participated in daily occupational therapy (30 minutes) and conventional, customized physiotherapy CG (60 minutes), IG (30 minutes). Only IG performed aerobic training by bicycles (30 minutes) aiming to reach low-to moderate training intensity. Outcome measures included peak oxygen uptake (VO2 peak), OUES, VO2-VT, functional exercise capacity 6-Minute Walking Test (6MWT) and Functional Independence Measure. Results: Thirty-five subjects completed the study. The VO2 peak uptake was very low in both groups (IG: 11.9 mL/kg/min, CG: 12.45 mL/kg/min) and did not improve after the program, but submaximal parameters such as VO2-VT (P < .01) and OUES (P < .001) have shown significant improvement, but only in IG regardless of insufficient impact on VO2 peak. Each participant in both groups was unable to permanently reach the moderate intensity zone. Functional Independence Measure changed for the better in both groups, but 6MWT only in the IG. Discussion and conclusions: Four-week exercise training even at low intensity by lower limb cycle ergometer may provide benefit on aerobic and functional capacity without improvement of VO2 peak on unconditioned chronic stroke patients.
Article
Full-text available
Objectives To describe new WHO 2020 guidelines on physical activity and sedentary behaviour. Methods The guidelines were developed in accordance with WHO protocols. An expert Guideline Development Group reviewed evidence to assess associations between physical activity and sedentary behaviour for an agreed set of health outcomes and population groups. The assessment used and systematically updated recent relevant systematic reviews; new primary reviews addressed additional health outcomes or subpopulations. Results The new guidelines address children, adolescents, adults, older adults and include new specific recommendations for pregnant and postpartum women and people living with chronic conditions or disability. All adults should undertake 150–300 min of moderate-intensity, or 75–150 min of vigorous-intensity physical activity, or some equivalent combination of moderate-intensity and vigorous-intensity aerobic physical activity, per week. Among children and adolescents, an average of 60 min/day of moderate-to-vigorous intensity aerobic physical activity across the week provides health benefits. The guidelines recommend regular muscle-strengthening activity for all age groups. Additionally, reducing sedentary behaviours is recommended across all age groups and abilities, although evidence was insufficient to quantify a sedentary behaviour threshold. Conclusion These 2020 WHO guidelines update previous WHO recommendations released in 2010. They reaffirm messages that some physical activity is better than none, that more physical activity is better for optimal health outcomes and provide a new recommendation on reducing sedentary behaviours. These guidelines highlight the importance of regularly undertaking both aerobic and muscle strengthening activities and for the first time, there are specific recommendations for specific populations including for pregnant and postpartum women and people living with chronic conditions or disability. These guidelines should be used to inform national health policies aligned with the WHO Global Action Plan on Physical Activity 2018–2030 and to strengthen surveillance systems that track progress towards national and global targets.
Article
Full-text available
Objectives: Major depressive disorder (MDD) is one of the most disabling mental illnesses and it has a significant impact on society. This review aims to provide updated scientific evidence about the epidemiology of MDD. Methods: A systematic literature review of the PubMed and MEDLINE databases was performed to identify articles on the prevalence of MDD and its correlates. The search was restricted to manuscripts published between January 2001 and December 2018. Results: Sixty-three articles were included in the review. The lifetime prevalence of MDD ranged from 2 to 21%, with the highest rates found in some European countries and the lowest in some Asian countries. The main sociodemographic correlates were separated/divorced marital status and female gender. Child abuse, intimate partner violence, and comorbidity with other physical and mental disorders also were consistently associated with MDD across the reviewed studies. Conclusions: MDD is a highly prevalent condition worldwide. There are remarkable interregional differences in the disorder’s prevalence, as well as in certain sociodemographic correlates. MDD is also highly comorbid with physical and mental health problems.
Article
Full-text available
Major depressive disorder (MDD), which is a leading psychiatric illness across the world, severely affects quality of life and causes an increased incidence of suicide. Evidence from animal as well as clinical studies have indicated that increased peripheral or central cytokine interleukin-6 (IL-6) levels play an important role in stress reaction and depressive disorder, especially physical disorders comorbid with depression. Increased release of IL-6 in MDD has been found to be a factor associated with MDD prognosis and therapeutic response, and may affect a wide range of depressive symptomatology. However, study results of the IL6 genetic effects in MDD are controversial. Increased IL-6 activity may cause depression through activation of hypothalamic-pituitary-adrenal axis or influence of the neurotransmitter metabolism. The important role of neuroinflammation in MDD pathogenesis has created a new perspective that the combining of blood IL-6 and other depression-related cytokine levels may help to classify MDD biological subtypes, which may allow physicians to identify the optimal treatment for MDD patients. To modulate the IL-6 activity by IL-6-related agents, current antidepressive agents, herb medication, pre-/probiotics or non-pharmacological interventions may hold great promise for the MDD patients with inflammatory features.