A Multi-level Life-span Characterization of Adult-depression and Effects of Medication and Exercise

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).

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.

Eligibility Criteria:
Inclusion Criteria:

1. Ages 20-39 (recruitment complete) and 60-79 years old (open to recruitment)
2. Major depressive disorder (MDD), single or recurrent, as diagnosed by the PRIME-MD
3. MADRS ≥ 15
4. In-town and available to commute to Oakland for a 12-week period
5. Study nurse practitioner approval to participate in a 12-week moderate intense exercise intervention
6. Eligible to undergo MRI

Exclusion Criteria:

1. Inability to provide informed consent.
2. Modified Mini-Mental Score (3MS) less than 84 or dementia based upon Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria including poor performance on the clinical neuropsychological battery, IQCODE, and all available clinical information.
3. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms.
4. Abuse of or dependence on alcohol or other substances within the past three months
5. High risk for suicide \[e.g., active suicidal ideation (SI) and/or current/recent intent or plan\] AND unable to be managed safely in the clinical trial (e.g., unwilling to be hospitalized). Urgent psychiatric referral will be made in these cases.
6. Contraindication to venlafaxine XR as determined by study physician including history of intolerance of venlafaxine XR in the study target dosage range (venlafaxine XR at up to 300 mg/day).
7. Inability to communicate in English (i.e., interview cannot be conducted without an interpreter; subject largely unable to understand questions and cannot respond in English).
8. Non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview)
9. Unstable/uncontrolled medical illness, including delirium, hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that are not under medical management.
10. Subjects taking psychotropic medications that cannot be safely tapered or discontinued prior to study initiation
11. If a patient failed a trial of venlafaxine (12 weeks of treatment with venlafaxine including at least 6 weeks on 300mg/day), he/she would not be eligible.
12. Other drugs that may affect the GABA system will be excluded (e.g., Kava, Valerian, Theanine, and GABA supplements).
13. The drug Linezolid (Zyvox) should be discontinued prior to study enrollment and should not be used during the study.
14. Exclusion criteria for MR scans include: cardiac pacemaker, aneurysm clip, cochlear implant, pregnancy, intrauterine device, shrapnel, history of metal fragments in the eye, neurostimulators, weight \>250 lbs., tinnitus, or claustrophobia.
15. Current medical condition or treatment for a medical condition that could affect balance, gait, or contraindicate participation in moderate intensity physical activity.
16. Observed gait condition or use of walking assisted device that would contraindicate use of treadmill for exercise testing and intervention.
17. Current congestive heart failure, angina, uncontrolled arrhythmia, or other symptoms indicative of an increased acute risk for a cardiovascular event; within the previous 12 months having a myocardial infarction, coronary artery bypass grafting, or angioplasty; conditions requiring chronic anticoagulation (i.e. recent or recurrent DVT).
18. Eating disorders that would contraindicate physical activity.
19. Report exercise on more than three days per week for greater than 20 minutes per day over the past three months.
20. Report plans to relocate to a location not accessible to the study site or having employment, personal, or travel commitments that prohibit attendance to at least 80 percent of the scheduled intervention sessions and all of the scheduled assessments.