This randomized controlled trial is designed to test the Vagal-gamma amino-butyric acid (GABA) Hypothesis that one of the mechanisms by which yoga-based practices improve mood and decrease anxiety is by correcting an autonomic system (ANS) imbalance with too much activity in the sympathetic nervous system (SNS) and too little activity in the parasympathetic nervous system (PNS). This imbalance is associated with under activity in the GABA system. It is hypothesized that yoga-based practices increase activity in the PNS by increasing respiratory sinus arrhythmia (RSA), which is associated with increased activity in the GABA system and decreased depressive and anxiety symptoms.

Subjects with Major Depressive Disorder (MDD) will be randomized into two treatment groups, a yoga group (YG) and a walking group (WG). After screening and Scan 1, each subject will be randomized to a 12-week yoga or walking intervention consisting of two group sessions and three homework sessions a week.The primary dependent variable will be brain gamma amino-butyric acid (GABA) levels measured using magnetic resonance spectroscopy (MRS) in two regions of interest (ROI)s: the thalamus and the anterior cingulate. GABA levels will be measured three times: Scan 1 prior to randomization, Scan 2 after the 12-week intervention, and immediately after Scan 2, subjects will participate in either the yoga intervention or walking intervention, followed immediately by Scan 3. The secondary dependent variable will be changes in depressive symptoms, mood and anxiety measured by valid and reliable psychological instruments obtained before each scan and at screening, week-4, week-8 and week-12. The third dependent variable will be respiratory sinus arrhythmia (RSA) a component of heart rate variability (HRV) that is an accurately index of vagal influences on the heart. RSA will be measured scan 1, pre and post an intervention session depending on group assignment at week 4, 8 and 12 evaluations, pre and post the yoga or walking intervention between Scan 2 and 3.

Aim 1: To complete 22 subjects in the yoga group and 22 subjects in the walking group for a total of 44 subjects with Major Depressive Disorder (MDD). Completion is defined at a baseline evaluation, a week-4 or week-8 evaluation and a week-12 evaluation with usable thalamic data for Scans 1, 2 and 3.

Aim 2. To measure changes in GABA levels over time using a mixed linear model analogue of repeated measures analysis-of-variance with independent groups in regional GABA levels in MDD subjects assigned to yoga and walking interventions.

Aim 3. To assess changes in psychological measurements and regional GABA levels over the course of the interventions using linear regression.

Aim 4. To assess changes in PNS using Respiratory Sinus Arrhythmia (RSA) over the course of the study using linear regression.

Aim 5. To assess changes in PNS, RSA and regional GABA levels over the course of the study using linear regression.

Inclusion Criteria:

• Subject is fluent in English.
• Subject understands the risks and benefits of the study as listed in the Post Consent Quiz.
• Females agree to use an acceptable form of birth control.
• Female had a negative pregnancy test or serum progesterone <= 0.30 ng/ml consistent with the non-luteal phase of the cycle prior to Scan 1.
• Subject meets criteria for Diagnosis of Major Depressive Disorder on the SCID.
• Subject had BDI-II score of at least 14 during screening.
• Subjects who are prescribed a stable dose of antidepressants at least three months with no anticipated changes in their medications for the course of the study (i.e. 3 months after enrollment).
• Subject who have been in a stable form of psychotherapy for three months with no anticipated changes in their psychotherapy for the course of the study (i.e. 3 months after enrollment).
• Subject had given contact information.
• Subject weighs up to 300 lbs at the discretion of the PI.
• Subject has completed all required screening instruments and evaluations.

Exclusion Criteria:

• Subject has a history of psychosis.
• Subject has a history of bipolar illness.
• Subject has a history of suicidal ideation with intent in the last year according to the Columbia Suicide Safety Rating (C-SSR) scale.
• Subject has a history of suicide attempt with attempt to injure in the last year according to the C-SSR.
• Subject who wishes to be treated for MDD with a new treatment during the study such as pharmacotherapy, or somatic therapy or psychotherapy.
• Subject has a contraindication to magnetic resonance evaluation (e.g. pregnancy, a cardiac pacemaker, ferrous implant including shrapnel, or intrauterine devices (IUDs) with copper, claustrophobia that would prevent scanning, some tattoos with black ink on the head including permanent eyeliner).
• Subject has a current mind-body practice (e.g., Tai Chi, Qigong, breathing practices, meditation) defined as more than 6 one-hour sessions in the last 6 months.
• Subject has a current prayer practice > 2 hours a week (prayer group does not count, only prayer practice).
• Subject participates in physical exercise >5 hours/week that is equivalent to or greater than 6 metabolic equivalents (METs) in intensity.
• Subject has been treated with mood stabilizers in the last three months (e.g., Topiramate, Valproic Acid, or Lithium).
• Subject has been treated with medications known to influence the GABA system in the last three months (e.g., anti-anxiety agents such as benzodiazepines, some sleeping aids such as Ambien, or sedative hypnotics).
• Subject uses nicotine regularly in the last three months.
• Subject has a neurologic condition that would in the opinion of the PI would affect the results of the magnetic resonance spectroscopy (MRS) scans.
• Subject has a medical condition that could compromise subject safety or the integrity of the study.
• Subject has a history of having more than 5 alcoholic drinks on 3 or more occasions in the prior three months.
• Subject in the opinion of the PI would not be expected to complete the study including scheduling related issues, whose safety would be jeopardized by participation or who would jeopardize the study protocol.
• Subject has an Axis-I diagnosis, other than depression that in the opinion of the PI would interfere with the subject's participation in this study.

There is a Data Safety Monitoring Plan that includes Independent Monitors with expertise in the areas of Clinical Care, Imaging and Statistics.