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).
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
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
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
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.
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.
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
6. Eligible to undergo MRI
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
3. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective
disorder, schizophreniform disorder, delusional disorder, or current psychotic
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
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
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
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
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.