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The goal of this clinical trial is to study how physical exercise works when applied to patients diagnosed with Major Depressive Disorder (MDD). The main questions it aims to answer are:
The experimental group will receive an exercise intervention as an add-on to their usual treatment (antidepressant treatment prescribed by the attending specialist). Researchers will compare to a control group, which will only receive standard treatment (antidepressant treatment prescribed by the attending specialist) and will be instructed to not change their usual physical activity. The aim is to see if a physical exercise intervention would induce a significant improvement in depressive symptoms and which mechanisms are responsible for this result.
Full description
RATIONALE, BACKGROUND AND CURRENT STATUS
Although it is well established that physical exercise (PE) is efficacious in treating mild to moderate depression [1], it remains underprescribed and there are large gaps in knowledge of the neurobiological mechanisms involved in the antidepressant effect of physical exercise. Depression is a common and disabling illness, affecting over 300 million people worldwide. Despite existing effective treatments for MDD, half of patients exhibit recurrences and about one-third are resistant to treatment [2]. Therefore there is an important need for new conceptual frameworks for understanding the pathophysiology of depression and for the implementation of cost-effective, acceptable to patients and feasible augmentation strategies for the treatment of MDD.
The underlying neurobiological mechanisms for exercise-related clinical improvement in depression remain understudied and require further investigation. From a physiological perspective, converging evidence suggests that exercise and antidepressant medication may alleviate depression through common neuromolecular mechanisms, including reduced inflammatory signalling [3] and increased expression of neuroplasticity [4]. There is substantial evidence about the contribution of low-grade inflammatory mechanisms to the pathophysiology of depression [5-7]. Increases in inflammation can elicit depression symptoms such as sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioural withdrawal [8].
Increasing evidence indicates that exercise exerts many benefits through activating Nrf2 signalling [9]. Nrf2 is a key master transcription factor that controls the expression of over 100 anti-oxidative and anti-inflammatory genes and that is dysfunctional in preclinical studies of depression. [10]. The protective effects of exercise are not seen when Nrf2 is blocked, supporting the role of Nrf2 in exercise-mediated neuroprotection [9]. To date, no exercise intervention studies have been conducted on Nrf2 signaling in humans.
There is a significant gap in the literature regarding the anti-inflammatory properties of exercise as add-on to antidepressant treatment. Well-conducted and more extensive studies are necessary to confirm any additive or synergistic effects between antidepressant drugs and physical exercise on inflammatory markers in MDD patients and its clinical relevance to treatment success or recurrence of MDD.
HYPOTHESIS
3.12 weeks of an exercise intervention in real-life conditions would lead to a significant better outcome of depressive symptoms (Hamilton depression rating scale) in MDD patients treated with combined exercise and standard treatment compared to MDD patients treated only with standard treatment.
4. A 12-week exercise intervention will be associated with significantly greater improvements in cognitive performance than standard treatment alone.
5. A 12-week exercise intervention will be associated with significantly greater improvements in functioning and well-being than standard treatment alone.
6. One year after the exercise intervention, there will remain antidepressant and procognitive effects.
7. The combination of physical exercise to the standard treatment of MDD will be better accepted by patients than standard treatment alone.
8. Increase in awareness and skills of health practitioners on the antidepressant effect of exercise will lead to the incorporation of exercise prescription into clinical practice.
AIMS
This project aims to:
DESIGN
It is proposed to carry out a multicenter, randomised, two-arm, parallel assignment, prospective, controlled trial of 12 weeks of exercise intervention, that includes a follow-up period of 1 year post-randomization.
Study arms:
Eligible patients will be randomly allocated (1:1) to the study arms, using a block randomization scheme. The exercise intervention will last 12 weeks and subjects will be assessed at 3-time points: at baseline before the randomization (T0); 12 weeks after the beginning of the intervention (T1) and 1 year after randomization (T2). The evaluation of the effect of the intervention will be blind. The clinical researchers that will assess patients at T1 and T2 will not know if the patients have been assigned to the EG or the CG. Patients will be instructed not to disclose their participation in the exercise program to the evaluators.
Exercise intervention
The exercise intervention program in real-life conditions will consist of two components:
Daily walking: Participants will be given an activity band (MiBand6) to self-monitor the number of steps they walk each day during the 12-week intervention period. The number of steps will be recorded with the activity band Miband6 and will automatically be sent to the exercise coach through the proper activity band configuration. The goal is set considering the superior number to the median of steps of the preceding week.
Weekly combined exercise sessions (aerobic + strength exercise): Participants will be scheduled to participate in 60-minute supervised online group sessions twice per week in a 12-week program. The exercise intervention will combine the use of elastic bands and the body weight. The exercise coach will supervise the exercise through a virtual connection allowing technical corrections and checking the proper performance of the activity. After 5 minutes of warm-up, the main part will begin, which consists of a training circuit with low-intensity strength exercises alternating work and rest times using rhythmic and melodic music preferred by the participants. Upper, lower and middle body exercises will alternate. The program will progress in intensity (using more resistant bands), work: rest ratio (starting at 30:30 and ending at 45:15), and technical difficulty of the exercises. At the end of the main part, there will be a cool-down and stretching for 5 minutes.
The effectiveness of this physical activity intervention will be assessed through:
STUDY SUBJECTS
A total of 124 MDD patients will be enrolled across a 3 year period. Patients' recruitment will be done in 4 participating centres in the region of Madrid (N=31 in each participating centre): Hospital La Princesa, Hospital La Paz, Hospital Ramón y Cajal and Hospital Principe de Asturias. All centres will follow the same research protocol.
ANALYSES
Differences between and within groups for continuous variables in the change from baseline to endpoint (12 weeks) and data concerning the 3-time points (baseline, 12 weeks, 1 year) will be analysed using a repeated-measurement, likelihood-based mixed-effect model with an unstructured variance matrix. Dichotomous variables will be assessed with odds ratios and χ2 tests. Potential moderators of the intervention will be examined by testing interaction terms between the intervention group and baseline characteristics (age, gender, clinical centre, treatment and baseline levels of BMI and physical activity). A generalised linear mixed model will be used to study changes over time in the study variables (clinical, cognitive, and biological biomarkers). Multiple regression models will be performed to explore predictive variables associated with clinical or cognitive changes. Confounding variables (concomitant pharmacological treatment and regular physical activity) will be controlled in the regression model. A compositional data analysis will be performed to explore associations between variables of interest and the composition of activity using multiple lineal regression models. All analyses will follow the intent-to-treat (ITT) principle. Statistical analyses will be performed using the IBM SPSS statistical software package (v.24.0, Chicago, IL, USA) and R software. The significance level will be set at P<0.05 and the confidence intervals will be calculated at 95%.
SAMPLE SIZE AND POWER ANALYSIS
Based on previous studies [11], a two-sided type 1 error probability of 5% with a Bonferroni adjusted α of .05/2 = .025 to allow for comparison of the 2 arms of the trial, as well as a minimal clinically relevant difference of 5 points on the Ham-D17, a standard deviation of 5.5 points, a β= .20 (power of 80%), and an anticipated dropout rate of 17% [12], we calculated that we needed a minimum of 124 patients (n=62/study arm), to detect clinically meaningful antidepressive changes after the physical exercise intervention.
LIMITATIONS
The study is designed as an add-on to usual MDD treatment which allows the apply a real-life conditions approach and will favour the transference of the results, however, the independent effect of exercise will not be assessed. For the same reason and to increase recruitment, homogeneity in the baseline pharmacological treatment will not be possible. An ideal design would select patients with similar severity characteristics to ascertain the clinical effect of exercise. However, it would limit the sample size and lead to an underpowered trial. This ecological approach would allow transference to clinical practice and acceptability by patients.
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124 participants in 2 patient groups
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Pilar López García, PhD; Javier Gómez Cumplido, PT, MSc
Data sourced from clinicaltrials.gov
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