Conditions: Depression Depressive Disorder, Major Depressive Disorder Unipolar Depression Major Depressive Disorder
Keywords: Exercise Physical activity GABA Venlafaxine fMRI Spectroscopy Reward system BDNF Sleep Cognitive function Biomarkers Aerobic exercise
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 31
Healthy volunteers: no

Brief summary:
This pilot study aims to test a model that predicts that enhanced neurotransmitter gamma-aminobutyric acid (GABA) function in reward and affect-regulation central nervous system (CNS) circuits mediates the antidepressant effects of exercise. State-of-the-art magnetic resonance (MR) imaging, cognitive assessment, accelerometry, genetic, and inflammatory biomarkers will be acquired through the coordination of efforts from several established research programs at Western Psychiatric Institute and Clinic. This pilot study will be used as a platform for testing a causal/mediating role of GABA interneurons in reward processing and affect regulation in humans. This pilot study is not powered for testing a full causal model, but rather is intended to test overall feasibility of the intervention and acquisition of measures (see specific aim 1 below). This is a necessary prerequisite for designing a larger more definitive study of the model, which will be a component of a future grant application. Additionally, the data from this study will be used to test the clinical efficacy of exercise as an adjunctive treatment for late life depression (LLD; Specific Aim 2), as well as imaging, cognitive, and sleep aims (Specific Aims 3 and 4).

Detailed description:
Specific Aims:

Aim 1: Establish the infrastructure, protocol, and procedures for recruiting, screening, enrolling, and maintaining a sample of 30 adults (both younger adults and older adults) with major depression in a 12-week exercise intervention. The primary aim is to establish both feasibility and proof-of-concept on a wide range of biologically and clinically relevant outcomes.

Aim 2: Examine whether the 12-week physical activity + pharmacotherapy intervention reduces depressive symptoms in both younger and older adults above and beyond that of treatment as usual (TAU). Hypothesis 1: In both younger and older adults the antidepressant properties of pharmacotherapy will be augmented when combined with aerobic exercise such that the combined intervention will have higher rates of response and remission compared to only pharmacotherapy treatment.

Aim 3: Examine whether the 12-week combined physical activity and pharmacotherapy intervention changes the structural morphology in specific subfields of the hippocampus. Hypothesis 1: The medication intervention will increase hippocampal volume in the dentate gyrus and carbonic anhydrase I (CA1), but combining aerobic exercise with pharmacotherapy will magnify the effects of exercise. Hypothesis 2: The effect on hippocampal volume will be larger for older versus younger adults Aim 4: Explore how the combination of pharmacotherapy and exercise (compared with pharmacotherapy and TAU) influences a range of brain and behavioral outcomes, including resting state brain dynamics, MR spectroscopic measures of GABA, sleep efficiency, and cognitive performance. Hypothesis 1: Antidepressant pharmacotherapy will alter resting state networks, increase GABA levels, and improve sleep efficiency and cognitive performance - but these effects will be greater when combined with an aerobic exercise intervention. Hypothesis 2: These effects will be moderated by age such that the effects will be greater in older adults, supporting a dissociation between depression in younger and adults, and providing justification for fully powered study to explore these models and treatment-predictive biomarkers.

Depression is a significant global public health concern; it is the second leading cause of disability worldwide and is currently estimated to affect 350 million people. Antidepressant medications have shown to be more effective than placebo in treating depression. However, for 20-40% of individuals suffering from depression the pharmacotherapy has a slow or inadequate response. Thus, identifying alternative treatments for depression is a public health priority.

Background:

Physical activity is emerging as one of the most promising non-pharmaceutical treatments for depression. Greater amounts of self-reported physical activity are associated with fewer depressive symptoms in epidemiological studies and randomized interventions find that participation in physical activity enhances mood in depressed populations. A Cochrane review of 32 randomized interventions concluded that participation in physical activity is effective for reducing depressive symptoms compared to either no treatment or to a control condition. Importantly, antidepressants and physical activity may work through similar biological pathways to influence both mood and cognitive function. In fact, both antidepressants and physical activity increase levels of Brain-derived neurotrophic factor (BDNF) in serum and hippocampus, may mitigate or reverse hippocampal atrophy, influence expression and kinetics of serotonin and GABA pathways, regulate brain network connectivity, alter inflammatory pathways, and improve sleep efficiency. Our proposal aims to characterize these effects from the genetic to the behavioral and cognitive level, and isolate the effects of physical activity from those of medication.

Significance:

If effective, physical activity could become a first line of treatment for depression, which might also help reduce cognitive deficits, job productivity, and risk of other psychiatric conditions. Furthermore, although physical exercise has shown promise in reducing depressive symptoms, researchers still do not understand the biological pathways by which it works. One of the leading hypotheses of depression is that disruptions in GABA systems underlies the deficits. In contrast, improvements in GABA signaling is one of the ways in which exercise may improve brain function and reduce depressive symptoms. Along this line, investigators hope to determine the type of exercise (aerobic versus stretching and toning) that can be promoted in the future to improve brain function and reduce depressive symptoms. Demonstrating these links could be an important first step for developing more effective treatment plans for those suffering from depression.

Arms:
arm 1: Venlafaxine (Effexor) Extended-Release (XR) comes in capsule form and is taken by mouth. Target dose will be 150mg/d, with a maximum dose of 300mg/d (response dependent) for a minimum of 12 weeks.

Exercise will include walking on a treadmill 1 hour 3 times/week for 12 weeks. Heart rate will be closely monitored during sessions. The intensity of the exercise will start at 50% of the age-based maximum for the first week and then increase and be maintained at 60-70% of the age-based maximum for the remainder of the intervention.

Lorazepam may be used in the study for patients who either are already on this drug or who need it for sleep and/or anxiety. This will be administered in pill form (2mg or less per 24 hours). arm 2: Venlafaxine (Effexor) XR comes in capsule form and is taken by mouth. Target dose will be 150mg/d, with a maximum dose of 300mg/d (response dependent) for a minimum of 12 weeks.

Lorazepam may be used in the study for patients who either are already on this drug or who need it for sleep and/or anxiety. This will be administered in pill form (2mg or less per 24 hours).

Interventions: intervention 1: Venlafaxine XR intervention 2: Aerobic Exercise intervention 3: Lorazepam
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: Lorazepam may be used in the study for patients who either are already on this drug or who need it for sleep and/or anxiety. Patients taking another benzodiazepine will be asked to convert from their current benzodiazepine to an equivalent dose of Lorazepam (2mg or less in 24 hours). This will be administered in pill form.

Protocol document: