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
Intervention: Venlafaxine XR; Aerobic Exercise; Lorazepam
Intervention description: 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.
Intervention MeSH terms: Lorazepam; Venlafaxine Hydrochloride
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 31.0
Sex: All
Minimum age: 60 Years
Maximum age: 79 Years
Healthy volunteers: No
Keywords: Exercise; Physical activity; GABA; Venlafaxine; fMRI; Spectroscopy; Reward system; BDNF; Sleep; Cognitive function; Biomarkers; Aerobic exercise

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).
    

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.