- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06387732
Mechanisms Underlying Antidepressant Effects of Physical Activity (LIFE)
The Mechanisms Underlying the Antidepressant Effects of Physical Activity
It is well established that any level of physical activity can help prevent and treat depression, with more strenuous activity having a greater effect. Understanding the mechanisms driving this antidepressant effect is important because it could allow exercise programmes to be made more effective, accessible, and targeted. Such knowledge could contribute to social prescribing, increasingly a priority for mental healthcare. Importantly, physical activity is highly scalable, low cost, well suited to early intervention, and has beneficial impacts on physical health co-morbidities. This trial may provide initial indications of whether there are sub-groups of depressed individuals who are particularly likely to benefit from physical activity, lead to strategies to personalise physical activity prescription based on motivational factors, and pave the way for augmentative approaches, for example combining physical activity with psychological interventions.
To date the mechanisms driving the antidepressant effects of physical activity in humans are poorly understood. Building on links between depressive symptoms, reward processing and dopamine, plus evidence from animal studies that physical activity is anti-inflammatory and boosts both dopamine and reward processing, the overarching aim of this trial is to understand the mechanisms underlying the effects of physical activity in depression, focusing on the concept of motivation.
The key objective is to conduct a randomised controlled trial (RCT) in N=250 depressed participants comparing aerobic exercise to a stretching/relaxation control condition, examining a range of mechanistic factors. The proposed trial will examine the impact of physical activity at multiple, linked potential levels of explanation: (1) immune-metabolic markers; (2) dopamine synthesis capacity; (3) activation in the brain's reward and effort processing circuitry;(4) effort-based decision making incorporating computational analysis; and (5) symptom networks based on fine-grained, daily measurements.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The primary objective is to conduct a randomised controlled trial (RCT) in N=250 depressed participants comparing aerobic exercise to a stretching/relaxation control condition, examining effects on a range of potential clinical and mechanistic factors: depressive symptoms; immune-metabolic function; activation in the brain's reward and effort processing circuitry using functional magnetic resonance imaging (fMRI); cognitive tasks, focusing on reward processing; and a subset (approximately one-third) of participants will complete L-6-[18F] fluoro-3,4-dihydroxyphenylalnine (18F-DOPA) positron emission tomography (PET).
The secondary objectives are to assess: (1) the degree to which changes in the mechanistic factors are related to changes in interest-activity symptoms of depression resulting from aerobic exercise; (2) whether baseline mechanistic or clinical factors are associated with symptomatic improvement measured by symptom questionnaires following the exercise intervention; (3) whether aerobic exercise-induced changes in the brain circuits underlying cognitive control overlap with those implicated in motivation.
The trial will use an RCT design, with depressed participants randomised to eight weeks of either 45 minutes aerobic exercise of moderate-to-vigorous intensity activity (experimental group: three times per week, N=125) or 45 minutes of non-aerobic stretching/guided relaxation (control group: three times per week, N=125). The target sample size following expected attrition is N~105 per arm. Participants will complete the trial in staggered cohorts, with no more than six participants per class.
Blood and saliva samples will be taken before the intervention at baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9) visits, to assess changes in immune-metabolic markers. Blood and saliva samples will also be collected at baseline and post-intervention from approximately 30 healthy controls.
Functional neuroimaging during effort-based decision-making and cognitive control will be taken at baseline and post-intervention. The same functional neuroimaging measures will also be collected at baseline and post-intervention from approximately 30 healthy controls.
Cognitive assessments will be completed online at baseline, every other week during the intervention (week 1, week 3, week 5, week 7), and post-intervention. The same cognitive assessments will also be collected at identical time-windows from approximately 30 healthy controls.
Questionnaire assessments will be completed online at baseline, every other week (week 2, week 4, week 6, week 8) and post-intervention. The same questionnaire assessments will be collected at baseline and post-intervention from approximately 30 healthy controls.
Accelerometers will measure physical activity continuously at baseline and during the intervention. Fitness testing will provide a measure of cardiovascular fitness at baseline and post-intervention visits. Daily depressive symptoms will be recorded using abbreviated scales using the Neureka smartphone app throughout the intervention. Three-monthly follow up of symptoms/cognition from baseline over six months will assess the durability of effects (week 21 and week 33).
In a subset of participants, approximately one-third of the participants will also complete a positron emission tomography (PET) scan pre-randomisation and at a visit during weeks 4-9, to assess dopamine synthesis capacity. The same PET scan will also be collected from approximately 30 healthy controls.
Study Type
Enrollment (Estimated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Emily Hird, PhD
- Phone Number: +44 20 7907 471
- Email: e.hird@ucl.ac.uk
Study Contact Backup
- Name: Larisa Duffy
- Phone Number: +44 20 7679 9282
- Email: l.duffy@ucl.ac.uk
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria will include:
- PHQ9≥15 (moderate depression).
- Current physical activity level below 30 min moderate physical activity, once per week.
- Fluency in English.
- Willingness to undergo the interventions.
- Age 18-60.
- Willing and able to provide written informed consent.
Exclusion Criteria will include:
- Medical contraindications to either intervention.
- Neurological illness.
- Past or current diagnosis of psychosis, bipolar disorder, or substance/alcohol use disorder, unless restricted to a depressive episode.
- Unable to complete self-administered cognitive or questionnaire assessments.
- Symptoms or cognitive impairment that would limit capacity to consent.
- Pregnancy.
- Regular use of anti-inflammatory medication (more than once per week).
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Aerobic exercise
Participants will be randomised to eight weeks of 45 min aerobic exercise of moderate-to-vigorous activity (experimental group: three times per week, N=125).
|
This will be delivered by coaches in a small group class format.
Participants will complete the trial in staggered cohorts, with no more than six participants per class.
Intervention activities will be tailored to each individual's own ability and fitness level.
|
Active Comparator: Stretching and relaxation
Participants will be randomised to eight weeks of 45 min aerobic exercise of stretching and relaxation (control group: three times per week, N=125).
|
This will be delivered by coaches in a small group class format.
Participants will complete the trial in staggered cohorts, with no more than six participants per class.
Intervention activities will be tailored to each individual's own ability and fitness level.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Patient Health Questionnaire-9 score
Time Frame: Post-intervention (week 9)
|
Depression symptoms will be measured using the Patient Health Questionnaire-9 (PHQ-9).
Minimum score is 0, maximum score is 27.
Higher scores mean a worse outcome.
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Post-intervention (week 9)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Physical activity
Time Frame: Baseline assessment period (between weeks -1 and 0) to post-intervention (week 9), and follow-up (weeks 21 and 33)
|
Physical activity will be measured continuously by accelerometers and between baseline, post-intervention and follow-up (weeks 21 and 33) using the International Physical Activity Questionnaire (IPAQ).
The minimum score is 0, and there is no maximum score.
A higher score means more physical activity.
|
Baseline assessment period (between weeks -1 and 0) to post-intervention (week 9), and follow-up (weeks 21 and 33)
|
Aerobic capacity: CPET
Time Frame: Baseline (between weeks -1 and 0) and post-intervention (week 9)
|
Aerobic capacity will be measured by the Cardiopulmonary Exercise Test (CPET), which is a physical fitness test.
|
Baseline (between weeks -1 and 0) and post-intervention (week 9)
|
Ecological Momentary Assessment
Time Frame: Baseline assessment period (between weeks -1 and 0) to post-intervention (week 9)
|
Brief daily depressive symptoms will be recorded throughout the intervention, using abbreviated scales, through the Neureka smartphone app.
Minimum score per item is -3, maximum score per item is 3. Higher scores mean a worse outcome.
|
Baseline assessment period (between weeks -1 and 0) to post-intervention (week 9)
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Inflammatory response (cytokines)
Time Frame: Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
|
Inflammatory cytokines (pg/mL) will assess changes in inflammatory responses.
|
Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
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Inflammatory response (genetic markers)
Time Frame: Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
|
Transcriptional markers (fold change) will assess changes in inflammatory responses.
|
Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
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Inflammatory response (flow cytometry immunophenotype)
Time Frame: Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
|
Flow cytometry immunophenotype (% cells) will assess changes in inflammatory responses.
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Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
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Neuroendocrine system
Time Frame: Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
|
Cortisol over the day (pg/mL) will assess changes in the neuroendocrine system.
|
Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
|
Metabolic function
Time Frame: Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
|
Metabolic blood markers (mg/dl) will assess changes in metabolic function.
|
Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
|
Dopamine synthesis capacity
Time Frame: Baseline (between weeks -1 and 0) and post-intervention (week 4-9)
|
In a subset of participants, dopamine synthesis capacity measured by 18F-DOPA PET will be taken.
|
Baseline (between weeks -1 and 0) and post-intervention (week 4-9)
|
Functional magnetic resonance imaging (fMRI) during cognitive tasks
Time Frame: Baseline (between weeks -1 and 0) and post-intervention (week 9)
|
Participants will complete effort-based decision making and cognitive control tasks during fMRI.
|
Baseline (between weeks -1 and 0) and post-intervention (week 9)
|
Online cognitive tasks
Time Frame: During every other week of the intervention (weeks -1/0, week 1, week 3, week 5, week 7, week 9)
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Participants will complete online cognitive tests of effort-based decision-making and cognitive control, alongside other tests of reward processing.
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During every other week of the intervention (weeks -1/0, week 1, week 3, week 5, week 7, week 9)
|
Depression symptoms
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8)
|
Depression symptoms will be measured by the Patient Health Questionnaire-9 (PHQ-9).
Minimum score is 0, maximum score is 27.
Higher scores mean a worse outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8)
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Anxiety (GAD7 score)
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Anxiety will be measured by the Generalised Anxiety Disorder Assessment (GAD7).
Minimum score is 0, maximum score is 21.
Higher scores mean a worse outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Anxiety (STAI score)
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Anxiety will be measured by the State-Trait Anxiety Inventory (STAI).
Minimum score is 20, maximum score is 80.
Higher scores mean a worse outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
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Anhedonia (SHAPS score)
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Anhedonia will be measured by the Snaith-Hamilton Pleasure Scale (SHAPS).
Minimum score is 14, maximum score is 56.
Higher scores mean a better outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
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Anhedonia (DARS score)
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Anhedonia will be measured by the Dimensional Anhedonia Rating Scale (DARS).
Minimum score is 0, maximum score is 68.
Higher scores mean a better outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
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Apathy
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Apathy will be measured by the Apathy Evaluation Scale (AES).
Minimum score is 18, maximum score is 72.
Higher scores mean a worse outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Fatigue
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Fatigue will be measured by the Fatigue Severity Scale (FSS).
Minimum score is 9, maximum score is 63.
Higher scores mean a worse outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
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Cognitive impairment
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Cognitive impairment will be measured by the British Columbia Cognitive Complaints Inventory (BC-CCI).
Minimum score is 0, maximum score is 18.
Higher scores mean a worse outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Self-efficacy
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Self-efficacy will be measured by the General Self-Efficacy Scale (GSES).
Minimum score is 8, maximum score is 40.
Higher scores mean a better outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
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Self-esteem
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Self-esteem will be measured by the Single-Item Self-Esteem Scale (SISES).
Minimum score is 1, maximum score is 7. Higher scores mean a better outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
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Sleep quality
Time Frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
|
Sleep quality will be measured by the Pittsburgh Sleep Quality Index (PSQI).
Minimum score is 0, maximum score is 21.
Higher scores mean a worse outcome.
|
During every other week of the intervention (weeks -1/0, week 2, week 4, week 6, week 8, week 9)
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Jonathan P Roiser, PhD, University College, London
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 161223
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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