Remission rates for Major Depressive Disorder (MDD) are low and unpredictable 
for any given antidepressant. No biological or clinical marker has demonstrated 
sufficient ability to match individuals to efficacious treatment. Biosignatures 
developed from the systematic exploration of multiple biological markers, which 
optimize treatment selection for individuals (moderators) and provide early 
indication of ultimate treatment response (mediators) are needed. The rationale 
and design of a multi-site, placebo-controlled randomized clinical trial of 
sertraline examining moderators and mediators of treatment response is 
described. The target sample is 300 participants with early onset (≤30 years) 
recurrent MDD. Non-responders to an 8-week trial are switched double blind to 
either bupropion (for sertraline non-responders) or sertraline (for placebo 
non-responders) for an additional 8 weeks. Clinical moderators include anxious 
depression, early trauma, gender, melancholic and atypical depression, anger 
attacks, Axis II disorder, hypersomnia/fatigue, and chronicity of depression. 
Biological moderator and mediators include cerebral cortical thickness, 
task-based fMRI (reward and emotion conflict), resting connectivity, diffusion 
tensor imaging (DTI), arterial spin labeling (ASL), electroencephalograpy (EEG), 
cortical evoked potentials, and behavioral/cognitive tasks evaluated at baseline 
and week 1, except DTI, assessed only at baseline. The study is designed to 
standardize assessment of biomarkers across multiple sites as well as institute 
replicable quality control methods, and to use advanced data analytic methods to 
integrate these markers. A Differential Depression Treatment Response Index 
(DTRI) will be developed. The data, including biological samples (DNA, RNA, and 
plasma collected before and during treatment), will become available in a public 
scientific repository.
CLINICAL TRIAL REGISTRATION: Establishing Moderators and Biosignatures of 
Antidepressant Response for Clinical Care for Depression (EMBARC). Identifier: 
NCT01407094. URL: http://clinicaltrials.gov/show/NCT01407094.