Inflammatory and Brain Mechanisms and Clinical and Cognitive Effects of an Exercise Intervention in Major Depressive Disorder: a Randomised Longitudinal Clinical Trial.
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Sponsor
- Enrollment
- 124
- Locations
- 8
- Primary Endpoint
- Inflammatory and oxidative stress biomarkers
Study Overview
Brief Summary
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:
- What are the antiinflammatory and oxidative stress and neural mechanisms involved in the antidepressant effects of exercise?
- How effective is a physical exercise program in MDD patients in real-life conditions?
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.
Detailed 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Single (Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •A diagnosis of Major Depressive Disorder (MDD) according to DSM-5 criteria (through the Mini International Neuropsychiatric Interview (MINI)
- •Severity of depression according to the Hamilton Depression Rating Scale 17 items (HAM-D17): minimum of 14 cut-off score of moderate depression.
- •Outpatient clinical care.
- •Current antidepressant treatment that will be maintained during the 12 weeks of the physical exercise intervention.
Exclusion Criteria
- •Diagnosis of any axis I diagnosis except for MDD;
- •Contraindications for Magnetic Resonance Imaging.
- •Antiinflammatory treatments or antibiotics within the week before randomisation.
- •Vaccines within the month before randomisation.
- •Fever (>38ºC) at the moment of study entry.
- •Pregnant women.
- •Alcohol or drug abuse.
Arms & Interventions
Control group (CG)
Major Depressive Disorder patients will only receive standard treatment (antidepressant treatment prescribed by the attending specialist) and will be instructed to not change their usual physical activity.
Intervention: Antidepressant medication (ADM) (Drug)
Exercise intervention group (EG)
Major Depressive Disorder patients will receive the exercise intervention for 12 weeks as an add-on to their usual treatment (antidepressant treatment prescribed by the attending specialist). They will gradually increase their levels of physical activity by daily walking and will conduct aerobic and muscle strength activities 2 days per week. The program will be supervised by a specialized mental health physiotherapist.
Intervention: Physical Exercise (Other)
Exercise intervention group (EG)
Major Depressive Disorder patients will receive the exercise intervention for 12 weeks as an add-on to their usual treatment (antidepressant treatment prescribed by the attending specialist). They will gradually increase their levels of physical activity by daily walking and will conduct aerobic and muscle strength activities 2 days per week. The program will be supervised by a specialized mental health physiotherapist.
Intervention: Antidepressant medication (ADM) (Drug)
Outcomes
Primary Outcomes
Inflammatory and oxidative stress biomarkers
Time Frame: 1. Before randomization; 2. 12-weeks after the beggining of intervention; 3. 1 year after randomization
Nrf2 activity will be measured in circulating monocytes and through transcriptomic analysis of redox and inflammation related genes. Plasma levels of hs C-reactive protein (CRP), interleukin 6 (hs-IL-6) and tumoral nechrosis factor alfa (hs- TNF-alfa) will be analyzed.
Brain imaging
Time Frame: 1. Before randomization; 2. 12 Weeks after the beggining of intervention
It will be evaluated using Magnetic Resonance Imaging. Four different sequences will be acquired: a) a T2-FLAIR sequence; b) a 3D T1w MPRAGE sequence; c) a Diffusion Weighted sequence and d) a T2 resting-state sequence. These data will be used to discard any neurological issues, to evaluate structural changes, and for other images coregistration, to evaluate the integrity of white matter and structural connectivity, and to evaluate functional connectivity.
Clinical evaluation
Time Frame: 1. Before Randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
The change in depression symptoms will be measured with the HAM-D17 scale. Duration of illness, number of episodes, current treatments, resistance antidepressant treatment index (Thase) will also be assessed.
Inflammatory and oxidative stress biomarkers
Time Frame: 1. Before randomization; 2. 12-weeks after the beggining of intervention; 3. 1 year after randomization
Nrf2 activity will be measured in circulating monocytes and through transcriptomic analysis of redox and inflammation related genes. Plasma levels of hs C-reactive protein (CRP), interleukin 6 (hs-IL-6) and tumoral nechrosis factor alfa (hs- TNF-alfa) will be analyzed.
Brain imaging
Time Frame: 1. Before randomization; 2. 12 Weeks after the beggining of intervention
It will be evaluated using Magnetic Resonance Imaging. Four different sequences will be acquired: a) a T2-FLAIR sequence; b) a 3D T1w MPRAGE sequence; c) a Diffusion Weighted sequence and d) a T2 resting-state sequence. These data will be used to discard any neurological issues, to evaluate structural changes, and for other images coregistration, to evaluate the integrity of white matter and structural connectivity, and to evaluate functional connectivity.
Clinical evaluation
Time Frame: 1. Before Randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
The change in depression symptoms will be measured with the HAM-D17 scale. Duration of illness, number of episodes, current treatments, resistance antidepressant treatment index (Thase) will also be assessed.
Secondary Outcomes
- Cognitive evaluation(1. Before Randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Functioning and Well-Being(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Muscle strength(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Cardiorespiratory fitness(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Anthropometric evaluation(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Metabolic biomarkers(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Nutrition habits(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Cognitive evaluation(1. Before Randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Functioning and Well-Being(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- 24-hours physical activity behaviors(1. Before Randomization; 2. 12 Weeks after the beggining of intervention)
- Muscle strength(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Cardiorespiratory fitness(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Anthropometric evaluation(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Metabolic biomarkers(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)
- Nutrition habits(1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization)