Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC)
The current study is designed to identify biomarkers for the prediction of differential treatment outcomes between the SSRi antidepressant sertraline (SeRT) and placebo (PBo) in a randomized trial for patients with MDD. in addition, a second stage will collect data to explore moderators and mediators of treatment outcomes between pharmacologically distinct active treatment arms: sertraline (SeRT), a serotonergic antidepressant or bupropion (BuP), a nonserotonergic antidepressant.
For the first stage, 400 depressed outpatients from 4 clinical sites will be randomized into one of the two treatment arms (SeRT: 200, PBo: 200).
Stage 1 Treatment Phase: outcomes will be assessed in terms of response rates (HRSD17) and tolerability (FiBSeR) at Stage 1 exit (up to 8 weeks of treatment). Treatment will be guided by clinician-rated symptom measures (the 16-item Quick inventory of Depressive Symptomatology-self-rated or QiDS-SR16) and global side effects measures (the Frequency, intensity, and Burden of Side effects Rating or FiBSeR) obtained at each treatment visit. Medication treatment visits will occur at baseline and at weeks 1, 2, 3, 4, 6, and 8 to ensure delivery of appropriate, vigorous, and tolerable pharmacotherapy. Those with unacceptable/intolerable side effects despite dose reduction may elect to enter Stage 2 Treatment Phase. Patients that are defined as nonresponders ([Less Than] 50% improvement) will enter Stage 2 Treatment Phase.
Stage 2 Treatment Phase: nonresponding patients will be crossed over, under double masked conditions. PBo nonresponders will receive SeRT, and SeRT nonresponders will receive BuP, again, treatment will be guided by self-rated symptom measures (the QiDS-SR16) and global side effects measures (FiBSeR) obtained at each treatment visit. Visit frequency, dose escalation, and treatment monitoring will follow the same procedures used in Stage 1, response and remission will be defined as a 50% improvement and HRSD17 [LessThanorequalTo] 7, respectively.
Follow-up: Patients will complete study-related assessments regarding mood, sleep, sexual function, feelings about home and work, depression and related symptoms, drug medications and non-drug treatment received, as well as possible suicidal thoughts, at weeks 26, 39, 52, 65, 78, 91, and 104 but will no longer be receiving study medications or compensation for these visits.
Start-up (Months 1-6): We will: (1) complete study manuals; (2) establish training/QC procedures; (3) pilot test data management; (4) distribute medications; (5) hire/train study personnel (6) obtain iRB approvals.
enrollment and intervention (Months 7-40): Study enrollment will begin at all 4 CSs after start-up, enrolling 400 participants over the ensuing 2.5 years. Patients will enter a 16-week treatment period with Stage 1 Treatment Phase being completed in the first 8 weeks and Stage 2 Treatment Phase completed in the next 8 weeks.
Data analysis and Reporting of Primary analyses (Months 41-48): The last participant will enter Stage 1 Treatment Phase at month 36, and will complete Stage 2 Treatment Phase at month 40. Final manuscripts reporting primary results will be submitted for publication by month 45.
of note, citalopram was the original SSRi chosen for this study. However, given recent FDa labeling changes due to increased cardiovascular risks, investigators decided to switch to SeRT for the evaluable sample. However, recruitment of a small subgroup of subjects (approximately 3 per site) for study feasibility assessments had been initiated prior to the FDa labeling changes for citalopram. as such, the eMBaRC Steering Committee decided to continue to utilize citalopram for the feasibility sample within FDa dosing guidelines with appropriate monitoring.
ancillary sub-studies were added:
(1) To collect additional biomarker data (actigraph data and leukocytes) on eMBaRC subjects at uTSW
(2) For an optional training program
* Adults, age 18-65
* Written informed consent obtained
* Outpatients with a current primary diagnosis of nonpsychotic chronic or recurrent MDD or dysthymic disorder per the SCID-I
* Age of onset of first episode of MDD/dysthymia < 30 years
* QIDS-SR scored of >/= 14 at Screening Visit and Randomization (Baseline) Visit
* No failed antidepressant trials of adequate dose and duration, as defined by the MGH-ATRQ, in the current episode
* Agrees to, and is eligible for, all biomarkers procedures (EEG/psychological testing, MRI, and blood draws)