Mechanisms Underlying Antidepressant Effects of Physical Activity

NCT06387732 | Recruiting DMC

• 1 other identifier: 161223
• Study Type: interventional
• Target: 250
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Depression

Keywords

Aerobic exercise; Effort; Decision-making; Cognitive control; Dopamine; Inflammation; Motivation

Outcome Measures

Primary Outcomes (1)

• 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 to week 14)

Secondary Outcomes (22)

• Physical activity

  Baseline assessment period (between weeks -1 and 0) to post-intervention (week 9 to week 14), and follow-up (weeks 21 and 33)

• Aerobic capacity: CPET

  Baseline (between weeks -1 and 0) and post-intervention (week 9 to week 14)

• Ecological Momentary Assessment

  Baseline assessment period (between weeks -1 and 0) to post-intervention (week 9 to week 14)

• Inflammatory response (cytokines)

  Baseline (between weeks -1 and 0), mid-intervention (week 3 or week 4), and post-intervention (week 9 to week 14)

• Inflammatory response (genetic markers)

  Baseline (between weeks -1 and 0), mid-intervention (week 3 or week 4), and post-intervention (week 9 to week 14)

Study Arms (2)

Aerobic exercise

EXPERIMENTAL

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).

Other: Aerobic exercise

Stretching and relaxation

ACTIVE COMPARATOR

Participants will be randomised to eight weeks of 45 min aerobic exercise of stretching and relaxation (control group: three times per week, N=125).

Other: Stretching and relaxation

Interventions

Aerobic exercise OTHER

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.

Aerobic exercise

Stretching and relaxation OTHER

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

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• PHQ9≥12 (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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• University College, London: lead
• King's College London: collaborator
• Queen Mary University of London: collaborator
• University of Dublin, Trinity College: collaborator

Study Sites (1)

Institute of Cognitive Neuroscience, University College London

London, WC1N 3AZ, United Kingdom

RECRUITING

MeSH Terms

Conditions

Depression; Inflammation

Interventions

Exercise

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Jonathan P Roiser, PhD

  University College, London

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Emily Hird, PhD

CONTACT

+44 20 7907 471; e.hird@ucl.ac.uk

Larisa Duffy

CONTACT

+44 20 7679 9282; l.duffy@ucl.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: The control arm is stretching and relaxation. Prior research indicates that participants have similar efficacy expectations regarding mild stretching and aerobic exercise, which will help to improve masking. Due to the nature of the interventions, it is not possible for the participants to be masked as to the intervention they are undergoing, but all study information will be agnostic about which intervention we expect to be more effective, and all analysis will be performed by blinded staff. The trial will assess expectations and preferences about the intervention conditions, allowing for sensitivity analyses.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The trial will use a single-site parallel group design with depressed participants randomised to eight weeks of either 45 minutes of aerobic exercise of moderate-to-vigorous 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).

Study Record Dates

• First Submitted: December 15, 2023
• First Posted: April 29, 2024
• Study Start: April 1, 2024
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: September 18, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Time Frame: Anonymised data will be available for sharing after publication of the trial results. Data will be available indefinitely.

Locations

GB (1)