Overview The study tests the hypothesis that an imbalance in the autonomic nervous system with to much sympathetic tone (Fight or Flight) and to little parasympathetic tone (rest, renewal and social engagement) and associated low activity in the neurotransmitter gamma aminobutyric acid (GABA) is associated with negative emotional states and may be a crucial underlying link between negative emotions and poor health such that the correction of these imbalances will be associated with decreased depressive symptoms in Veterans with Major Depressive Disorder (MDD). Study Design: This is a Phase 2, longitudinal, efficacy, randomized controlled trial. Veterans with MDD will be evaluated for eligibility and randomized to 12-week intervention providing two-sessions per week of either an intervention of yoga and coherent breathing at five breaths per minute or walking at 2.5 miles an hour, such that the groups are matched for metabolic demand, interaction with research staff and group effect. Depression scales will be collected at baseline and weeks 4, 8, and 12. Mood scales and RSA will be collected at baseline and pre and post interventions at weeks 4, 8, and 12. Magnetic resonance spectroscopy (MRS) data for thalamic GABA levels will be collected at baseline (Scan 1), after the 12-week intervention (Scan 2) which is immediately followed by the assigned intervention and Scan 3. The primary outcome measure is depression symptoms assessed using established rating scales. The secondary outcome measure is the thalamic GABA levels. The tertiary outcome measure is Respiratory Sinus Arrhythmia (RSA), a measure of high frequency Heart Rate Variability and a marker of parasympathetic tone. Evaluations are designed to address changes over the course of the study, and acute changes before and after interventions at week 4, 8, and 12 evaluations. Instruments: Depression scales include the Hamilton Rating Scale for Depression-17 (HDRS) and the Beck Depression Inventory II (BDI-II). Mood scales include the Spielberger State -Trait Anxiety Inventory (STAI) and the Exercise -Induced Feeling Inventory (EIFI). Post Traumatic Stress Disorder (PTSD) scales include the Clinician Administered Posttraumatic Stress Scale (CAPS) and the PTSD Check List ? Civilian (PCL-C). Inclusion Criteria: The study will include 18 to 65 year old males and females Veterans with a current diagnosis of MDD who have a HDRS scores ? to 14 at screening. If subjects have been taking a stable dose of antidepressants that target a monoamine system for at least three months with no anticipated changes during the study, they will be allowed to continue their medication. Exclusion Criteria: The following are not allowed: history of psychosis or bipolar illness; history of suicidal ideation with intent in the last year; current mind-body practice (e.g., yoga, Tai Chi, Qigong, breathing practices, or meditation); more than three current criteria for Alcohol or Substance Use Disorder using DSM-V criteria; a current Substance Use Disorder, a neurologic or medical condition that could compromise subject safety or the integrity of the study. Blinding: Individuals scoring the depression scales, or analyzing the MRS and RSA data will be blind to group assignment. Hypothesis: I.a: The yoga group but not the walking group will show decreased in depressive symptoms on the HDRS and BDI-II from screening to week 12. 1.b: Subjects who are still depressed at baseline despite treatment with a stable dose (> 3 months) of antidepressants treatment will show decreased depressive symptoms in the yoga but not the walking group. 1.c: If present at baseline, there will be a greater decrease in PTSD symptoms on the CAPS in the yoga compared to the walking group. 2: There will be an increase in GABA levels over the course of the three scans in the yoga but not the walking group. 3: Over the course of the intervention and from pre to post-intervention at weeks 4, 8, and 12 there will be an improvement in the mood scales (STAI and EIFI), and increase in RSA in the yoga but not the walking group.
! The proposed study addresses a gap regarding the need for effective Major Depressive Disorder (MDD) treatments and the 40% of individuals treated with antidepressant medications that do not achieve full remission. This study tests a novel approach for treating MDD in a Randomized Control Trial (RTC) using yoga versus walking interventions to correct an imbalance in the Autonomic Nervous System; an over active Sympathetic Nervous System (fight or flight) an underactive Parasympathetic Nervous System (PNS) (rest, renewal and social engagement) and associated under activity in the neurotransmitter, gamma aminobutyric acid (GABA). This novel approach is complimentary to the use of antidepressant medications that primarily target the monoamine systems. Low activity in the PNS and GABA systems are also found in MDD, PTSD, and Alcohol Use Disorder, disorders representing a high healthcare burden in the Veteran population. This intervention has potential to provide relief for MDD and other disorders relevant the Veteran population. !