Ignite Creation Date:
2024-06-16 @ 11:52 AM
Last Modification Date:
2024-10-26 @ 3:31 PM
Study NCT ID:
NCT06450704
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-10
First Post:
2024-06-05
Brief Title:
Cerebral and Anti-inflammatory Response Through Exercise - Mechanisms In Depressive Disorders
Sponsor:
Fundación de Investigación Biomédica - Hospital Universitario de La Princesa
Organization:
Fundación de Investigación Biomédica - Hospital Universitario de La Princesa
Study Overview
Official Title:
Inflammatory and Brain Mechanisms and Clinical and Cognitive Effects of an Exercise Intervention in Major Depressive Disorder a Randomised Longitudinal Clinical Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CARE-MIND
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
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
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
312 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 patients 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 11 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 3030 and ending at 4515 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 ie 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 v6134 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 N31 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 v240 Chicago IL USA and R software The significance level will be set at P005 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 052 025 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 55 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 n62study 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
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
312 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 patients 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 11 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 3030 and ending at 4515 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 ie 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 v6134 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 N31 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 v240 Chicago IL USA and R software The significance level will be set at P005 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 052 025 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 55 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 n62study 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None