Mechanisms Underlying Antidepressant Effects of Physical Activity

Depression Clinical Trial

— LIFE  

Official title:

The Mechanisms Underlying the Antidepressant Effects of Physical Activity

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06387732
• Other study ID #: 161223
• Status: Not yet recruiting
• Phase: N/A
• Start date: June 2024
• Est. completion date: January 2028

Study information

• Verified date: April 2024
• Source: University College, London
• Contact: Emily Hird, PhD
• Phone: +44 20 7907 471
• Email: e.hird[@]ucl.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 250
• Est. completion date: January 2028
• Est. primary completion date: August 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria will include:

1. PHQ9=15 (moderate depression).

2. Current physical activity level below 30 min moderate physical activity, once per week.

3. Fluency in English.

4. Willingness to undergo the interventions.

5. Age 18-60.

6. Willing and able to provide written informed consent.

Exclusion Criteria will include:

1. Medical contraindications to either intervention.

2. Neurological illness.

3. Past or current diagnosis of psychosis, bipolar disorder, or substance/alcohol use disorder, unless restricted to a depressive episode.

4. Unable to complete self-administered cognitive or questionnaire assessments.

5. Symptoms or cognitive impairment that would limit capacity to consent.

6. Pregnancy.

7. Regular use of anti-inflammatory medication (more than once per week).

Related Conditions & MeSH terms

• Depression

Intervention

Other:
• Aerobic exercise
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.
• Stretching and relaxation
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.

Locations

Country	Name	City	State
n/a

Sponsors (4)

Lead Sponsor	Collaborator
University College, London	King's College London, Queen Mary University of London, University of Dublin, Trinity College

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Patient Health Questionnaire-9 score	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.	Post-intervention (week 9)
Secondary	Physical activity	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)
Secondary	Aerobic capacity: CPET	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)
Secondary	Ecological Momentary Assessment	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)
Secondary	Inflammatory response (cytokines)	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)
Secondary	Inflammatory response (genetic markers)	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)
Secondary	Inflammatory response (flow cytometry immunophenotype)	Flow cytometry immunophenotype (% cells) will assess changes in inflammatory responses.	Baseline (between weeks -1 and 0), mid-intervention (week 3), and post-intervention (week 9)
Secondary	Neuroendocrine system	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)
Secondary	Metabolic function	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)
Secondary	Dopamine synthesis capacity	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)
Secondary	Functional magnetic resonance imaging (fMRI) during cognitive tasks	Participants will complete effort-based decision making and cognitive control tasks during fMRI.	Baseline (between weeks -1 and 0) and post-intervention (week 9)
Secondary	Online cognitive tasks	Participants will complete online cognitive tests of effort-based decision-making and cognitive control, alongside other tests of reward processing.	During every other week of the intervention (weeks -1/0, week 1, week 3, week 5, week 7, week 9)
Secondary	Depression symptoms	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)
Secondary	Anxiety (GAD7 score)	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)
Secondary	Anxiety (STAI score)	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)
Secondary	Anhedonia (SHAPS score)	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)
Secondary	Anhedonia (DARS score)	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)
Secondary	Apathy	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)
Secondary	Fatigue	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)
Secondary	Cognitive impairment	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)
Secondary	Self-efficacy	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)
Secondary	Self-esteem	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)
Secondary	Sleep quality	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)