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

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.

Depression, Depressive Disorder, Major, Depressive Disorder, Unipolar Depression, Major Depressive Disorder

Exercise, Physical activity, GABA, Venlafaxine, fMRI, Spectroscopy, Reward system, BDNF, Sleep, Cognitive function, Biomarkers, Aerobic exercise

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).

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).

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.

Study completers will be classified as remitters vs. non-remitters. Remission will be defined as a MADRS score of 10 or less for at least two consecutive assessments. The MADRS will also be used to assess clinical response throughout the trial and to determine final medication dosage. At the end of week 6, those with a MADRS score greater than 10 will have the venlafaxine XR increased from 150 mg/d to a maximum of 300 mg/d.

Blood samples were collected to assess biomarkers, but funding is not yet available to perform analyses.

Blood samples were collected to assess biomarkers, but funding is not yet available to perform analyses.

This will be used to acquire objective information about physical activity. This armband is worn around the upper arm (left triceps) for 1 week and collects information about skin temperature, galvanic skin response, heat flux, and motion via a 3-axis accelerometer. This information is used in an algorithm to determine energy expenditure (EE). The device has a resolution of 1-minute indicating that we can acquire the above information on a minute-by-minute basis, which will allow us to determine both duration and intensity of activity during a normal week. Higher values indicate higher levels of activity.

Cardiorespiratory fitness was measured via submaximal VO2 on a motorized treadmill while measuring oxygen utilization via Parvo Medics True one metabolic cart. The submaximal test followed a modified Balke protocol in which speed remained constant with the intensity being increased every two minutes via a raise of 2.0% of the incline. The speed was an agreed upon speed between participant and staff (between 2.0 and 4.0 mph). The submaximal VO2 was stopped when participant reached 85% of age predicted maximal heart rate (220 - age), rating of perceived exertion (RPE) equal to or greater than 15 for those who have blunted heart rate response due to beta block medication, or volitional termination by participant. Vital signs were monitored throughout the test and cool down period. Peak VO2 values for this cohort ranged from 14.04 to 36.48 ml/kg/min, with higher values correlated to higher fitness level.

Brain imaging conducted with a 7 Tesla scanner. Of particular interest were changes in hippocampal volume, GABA, and glutamate. The changes regarding hippocampal volumes are reported below. This measurement is reported in mm^3, with higher numbers indicating higher levels of gray matter in the hippocampal region. Volume is combined between right and left hemispheres. GABA and glutamate are not reported. The method used to obtain the data was being piloted for this study, and due to methodological challenges, the data is not considered to be accurate and therefore cannot be analyzed/shared.

The battery evaluates several cognitive domains. The Wechsler Adult Intelligence Scale, 4th ed. Digit Span subtest assesses attention and working memory. The Repeatable Battery of Neuropsychological Status (RBANS) measures Immediate and Delayed Memory, Attention, Language Abilities, and Visuospatial Functioning. Total index scores range from 40-155. The California Verbal Learning Test, 2nd Ed. (CVLT) assesses non-contextual verbal learning and memory. Z-scores are calculated for each of the constructs assessed by the CVLT. Subtests from the Deli-Kaplan Executive Function System (D-KEFS) assess aspects of executive functioning, including set-shifting (Trail Making Test Conditions 4 and 5: scaled score ranging from 0-19) and inhibition (Color-Word Interference Test Condition 3: weighted scaled score ranging from 1-19). Given that standardized scores are calculated for each of the neuropsychological measures, higher scores always indicate better cognitive functioning.

Inclusion Criteria: Ages 20-39 (recruitment complete) and 60-79 years old (open to recruitment) Major depressive disorder (MDD), single or recurrent, as diagnosed by the PRIME-MD MADRS ≥ 15 In-town and available to commute to Oakland for a 12-week period Study nurse practitioner approval to participate in a 12-week moderate intense exercise intervention Eligible to undergo MRI Exclusion Criteria: Inability to provide informed consent. 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. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms. Abuse of or dependence on alcohol or other substances within the past three months 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. 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). 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). Non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview) Unstable/uncontrolled medical illness, including delirium, hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that are not under medical management. Subjects taking psychotropic medications that cannot be safely tapered or discontinued prior to study initiation 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. Other drugs that may affect the GABA system will be excluded (e.g., Kava, Valerian, Theanine, and GABA supplements). The drug Linezolid (Zyvox) should be discontinued prior to study enrollment and should not be used during the study. 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. Current medical condition or treatment for a medical condition that could affect balance, gait, or contraindicate participation in moderate intensity physical activity. Observed gait condition or use of walking assisted device that would contraindicate use of treadmill for exercise testing and intervention. 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). Eating disorders that would contraindicate physical activity. Report exercise on more than three days per week for greater than 20 minutes per day over the past three months. 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.

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