A Multi-level Life-span Characterization of Adult-depression and Effects of Medication and Exercise
Condition: Depression; Depressive Disorder, Major; Depressive Disorder; Unipolar Depression; Major Depressive Disorder
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Venlafaxine XR; Aerobic Exercise; Lorazepam
Intervention type(s): Drug; Other; Drug
Intervention description(s): 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.
Other intervention name(s): Effexor XR; Physical Activity; Cardiovascular Exercise; Ativan
Intervention MeSH terms: Lorazepam; Venlafaxine Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Exercise; Physical activity; GABA; Venlafaxine; fMRI; Spectroscopy; Reward system; BDNF; Sleep; Cognitive function; Biomarkers; Aerobic exercise