Mechanisms Underlying Antidepressant Effects of Physical Activity

University College, London250 enrolled

Overview

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.

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 week 4), and post-intervention (week 9 to week 14) 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) and post-intervention (week 9 to 14). 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 14, to assess dopamine synthesis capacity. The same PET scan will also be collected from approximately 30 healthy controls.

Outcomes

Primary Outcomes

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.

Time frame: Post-intervention (week 9 to week 14)

Secondary Outcomes

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.

Time frame: 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

Aerobic capacity will be measured by the Cardiopulmonary Exercise Test (CPET), which is a physical fitness test.

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

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.

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

Inflammatory response (cytokines)

Inflammatory cytokines (pg/mL) will assess changes in inflammatory responses.

Time frame: 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)

Transcriptional markers (fold change) will assess changes in inflammatory responses.

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

Inflammatory response (flow cytometry immunophenotype)

Flow cytometry immunophenotype (% cells) will assess changes in inflammatory responses.

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

Neuroendocrine system

Cortisol over the day (pg/mL) will assess changes in the neuroendocrine system.

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

Metabolic function

Metabolic blood markers (mg/dl) will assess changes in metabolic function.

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

Dopamine synthesis capacity

In a subset of participants, dopamine synthesis capacity measured by 18F-DOPA PET will be taken.

Time frame: Baseline (between weeks -1 and 0) and post-intervention (week 4-9 to week 14)

Functional magnetic resonance imaging (fMRI) during cognitive tasks

Participants will complete effort-based decision making and cognitive control tasks during fMRI.

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

Online cognitive tasks

Participants will complete online cognitive tests of effort-based decision-making and cognitive control, alongside other tests of reward processing.

Time frame: During every other week of the intervention (weeks -1/0, week 1, week 3, week 5, week 7, week 9 to week 14)

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.

Time frame: During every other week of the intervention (weeks -1/0, week 2, week 4, week 6)

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.