Cerebral and Anti-inflammatory Response Through Exercise - Mechanisms In Depressive Disorders

Major Depressive Disorder Clinical Trial

— CARE-MIND  

Official title:

Inflammatory and Brain Mechanisms and Clinical and Cognitive Effects of an Exercise Intervention in Major Depressive Disorder: a Randomised Longitudinal Clinical Trial.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06450704
• Other study ID #: 5561
• Status: Not yet recruiting
• Phase: N/A
• Start date: September 1, 2024
• Est. completion date: December 31, 2026

Study information

• Verified date: June 2024
• Source: Fundación de Investigación Biomédica - Hospital Universitario de La Princesa
• Contact: Javier Gómez Cumplido, PT, MSc
• Phone: (+34) 633467602
• Email: javgom08[@]ucm.es
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

1. A physical exercise intervention as add-on to the conventional treatment of MDD will lead to antiinflammatory effects and less oxidative stress via Nrf2.

2. The exercise intervention would induce functional and structural changes in the brain of MDD patients treated with combined exercise and standard treatment.

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:

1. Analyze the effects of physical exercise on inflammation and oxidative stress, studying the activity levels of Nrf2 before and after the exercise intervention in MDD patients.

2. Study volumetric changes and cortical thickness, structural and functional connectivity and microstructural changes in the white matter in the brain after a 12-week exercise intervention.

3. Compare the antidepressant effect of a 12-week exercise intervention in real-life conditions combined with standard treatment to standard treatment and to study the change in symptom severity after the exercise intervention.

4. Explore changes in the cognitive performance of MDD patients after a 12-week exercise intervention.

5. Assess functioning and well-being after a 12-week exercise intervention in MDD patients.

6. Investigate if the clinical and cognitive changes persist 1 year after the beginning of the exercise intervention.

7. Evaluate the patient´s acceptability of an exercise-based intervention.

8. Increase awareness and skills of health practitioners on the anti-depressive effect of exercise.

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:

1. Exercise intervention group (EG): MDD patients will receive the exercise intervention as an add-on to their usual treatment (antidepressant treatment prescribed by the attending specialist).

2. Control group (CG): MDD patients will only receive standard treatment (antidepressant treatment prescribed by the attending specialist) and will be instructed to not change their usual physical activity.

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) (table 1). 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:

1. to gradually increase the levels of physical activity by daily walking

2. additionally, participants will conduct aerobic and muscle strength activities 2 days per week. The program will be supervised by a physical education and sports professional with more than 10 years of experience in promoting physical exercise in MDD and several mental disorders patients.

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:

1. Online supervision twice a week by a physical education and sports professional during the combined exercise sessions. Additionally, this professional will receive the number of steps the participants have walked every day of the week through the activity band Miband6 and will send a weekly message to the participants to propose an individualized goal of steps for the upcoming week. Every two weeks, the same professional will contact the participants to check their progress and to analyze strategies to achieve the goals regarding the number of steps.

2. Movement-related behaviours (i.e., physical activity, sedentary behaviour, and sleep time) will be measured by the wrist-worn tri-axial accelerometer ActiGraph GT9X Link (Pensacola, FL, USA). The accelerometer will be worn 24 hours over 7 days at the onset of the exercise intervention and 7 days post-intervention. Sleep time, sedentary activity, and mild and moderate-intense physical activity will be objectively estimated using the data monitored by multiple sensors and using specific algorithms (ActiLife software v6.13.4; ActiGraph Corp., LLC).

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 124
• Est. completion date: December 31, 2026
• Est. primary completion date: September 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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; Ongoing alcohol use and drug use will be assessed through the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Abuse Screening Test (DAST-10) respectively since it may affect inflammation.

• Excessive physical exercise assessed through certain questions extracted from the European Prospective Investigation into Cancer and Nutrition Physical Activity questionnaire.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Inflammatory Response
• Major Depressive Disorder

Intervention

Other:
• Physical Exercise
Daily walking. Participants will be given an activity band to self-monitor the number of steps they walk each day during the 12-week intervention period. Each participant must reach a certain number of daily steps with a progressive goal adjusted to the number of steps from the previous week. The goal is set considering the superior number to the median of steps of the preceding week. Weekly combined exercise sessions (aerobic + strength exercise) 2 sessions of 60 minutes per week in a 12-week program. The exercise intervention will combine the use of elastic bands and the body weight. First, 5 minutes of warm-up; second, training circuit with low-intensity strength exercises alternating work and rest times using rhythmic music. Upper, lower and middle body exercises will alternate. The program will progress in intensity, work: rest ratio, and technical difficulty of the exercises. At the end of the main part, there will be a cool-down and stretching for 5 minutes.

Locations

Country	Name	City	State
Spain	Hospital Universitario de La Princesa	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Príncipe de Asturias	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid

Sponsors (7)

Lead Sponsor	Collaborator
Fundación de Investigación Biomédica - Hospital Universitario de La Princesa	Centro de Investigación Biomédica en Red de Salud Mental, Hospital Universitario La Paz, Hospital Universitario Principe de Asturias, Hospital Universitario Ramon y Cajal, Quirón Madrid University Hospital, Universidad Autonoma de Madrid

Country where clinical trial is conducted

Spain, 

References & Publications (12)

Dishman RK, Berthoud HR, Booth FW, Cotman CW, Edgerton VR, Fleshner MR, Gandevia SC, Gomez-Pinilla F, Greenwood BN, Hillman CH, Kramer AF, Levin BE, Moran TH, Russo-Neustadt AA, Salamone JD, Van Hoomissen JD, Wade CE, York DA, Zigmond MJ. Neurobiology of exercise. Obesity (Silver Spring). 2006 Mar;14(3):345-56. doi: 10.1038/oby.2006.46. — View Citation

Done AJ, Traustadottir T. Nrf2 mediates redox adaptations to exercise. Redox Biol. 2016 Dec;10:191-199. doi: 10.1016/j.redox.2016.10.003. Epub 2016 Oct 14. — View Citation

Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010 Mar 1;67(5):446-57. doi: 10.1016/j.biopsych.2009.09.033. Epub 2009 Dec 16. — View Citation

Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009 Feb;71(2):171-86. doi: 10.1097/PSY.0b013e3181907c1b. Epub 2009 Feb 2. — View Citation

Krogh J, Saltin B, Gluud C, Nordentoft M. The DEMO trial: a randomized, parallel-group, observer-blinded clinical trial of strength versus aerobic versus relaxation training for patients with mild to moderate depression. J Clin Psychiatry. 2009 Jun;70(6):790-800. doi: 10.4088/jcp.08m04241. — View Citation

Mathur N, Pedersen BK. Exercise as a mean to control low-grade systemic inflammation. Mediators Inflamm. 2008;2008:109502. doi: 10.1155/2008/109502. Epub 2009 Jan 11. — View Citation

Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan;16(1):22-34. doi: 10.1038/nri.2015.5. — View Citation

Ravindran AV, Balneaves LG, Faulkner G, Ortiz A, McIntosh D, Morehouse RL, Ravindran L, Yatham LN, Kennedy SH, Lam RW, MacQueen GM, Milev RV, Parikh SV; CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments. Can J Psychiatry. 2016 Sep;61(9):576-87. doi: 10.1177/0706743716660290. Epub 2016 Aug 2. — View Citation

Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905. — View Citation

Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull. 2014 May;140(3):774-815. doi: 10.1037/a0035302. Epub 2014 Jan 13. — View Citation

Stubbs B, Vancampfort D, Rosenbaum S, Ward PB, Richards J, Soundy A, Veronese N, Solmi M, Schuch FB. Dropout from exercise randomized controlled trials among people with depression: A meta-analysis and meta regression. J Affect Disord. 2016 Jan 15;190:457-466. doi: 10.1016/j.jad.2015.10.019. Epub 2015 Oct 29. — View Citation

Zuo C, Cao H, Song Y, Gu Z, Huang Y, Yang Y, Miao J, Zhu L, Chen J, Jiang Y, Wang F. Nrf2: An all-rounder in depression. Redox Biol. 2022 Dec;58:102522. doi: 10.1016/j.redox.2022.102522. Epub 2022 Oct 31. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Inflammatory and oxidative stress biomarkers	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.	1. Before randomization; 2. 12-weeks after the beggining of intervention; 3. 1 year after randomization
Primary	Brain imaging	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.	1. Before randomization; 2. 12 Weeks after the beggining of intervention
Primary	Clinical evaluation	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.	1. Before Randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
Primary	24-hours activity behaviors	Physical activity, sedentarism and sleep will be objectively measured using a multi-sensor monitor (ActiGraph GT9X Link, Pensacola, FL, USA) over a 24-hour 7 days period at the onset of the exercise intervention and 7 days post-intervention. Only participants who carry the monitor for at least 95% of the day (1368 minutes) will be included in the analysis. This monitor is worn as a watch and will be placed on the non-dominant wrist. Daily steps will be recorded through the activity band (MiBand6).	1. Onset of the intervention; 2. 7 Days after intervention
Primary	Physical activity information	It will be assessed through the European Prospective Investigation into Cancer and Nutrition physical activity questionnaire (EPIC).	1. Before Randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
Secondary	Cognitive evaluation	Learning and verbal memory through the Hopkins Verbal Learning Test-Revised (HVLT-R); executive functioning through the Trail Making Test part B (TMT-B) and the short form of the Wisconsin Card Sorting Test (WCST-64); processing speed through the Salthouse Perceptual Comparison Test (SPCT).	1. Before Randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
Secondary	Functioning and Well-Being	The patient's functioning will be assessed through the WHO-DAS-II and well-being will be measured with the Cantrill ladder.	1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
Secondary	Muscle strength	It will be directly measured through a handheld dynamometer (TKK 5401 Grip-D, Takey, Tokyo, Japan) and a dynamometer for the upper and lower extremities (Lafayette Instruments dynamometer, Lafayette, Ind).	1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
Secondary	Cardiorespiratory fitness	It will be measured with an established test protocol on a bicycle ergometer. During a ramp protocol workload increases of 1 W every 6 s will be applied starting from an initial load of 0 W, with a pedal cadence of 60 -70 rpm throughout the test.	1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
Secondary	Anthropometric evaluation	Weight will be assessed through a stadiometer (SECA) and waist circumference with a metric tape (Harpenden anthropometric tape, Holtain Ltd). Body Mass Index, waist-to-hip ratio and blood pressure also will be assessed.	1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
Secondary	Metabolic biomarkers	Serum levels of glucose, glycosylated haemoglobin and lipid profile.	1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization
Secondary	Nutrition habits	It will be assessed with the Food Frequency Questionnaire (FFQ).	1. Before randomization; 2. 12 Weeks after the beggining of intervention; 3. 1 Year after randomization