Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression

Study ID
STU 092010-151

Cancer Related

Healthy Volunteers

Study Sites

  • UT Southwestern-Other
  • CTRC Outpatient

Kathy Shores-Wilson

Principal Investigator
Madhukar Trivedi, M.D.

Official Title

Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) for Depression

Brief Overview

This study will examine multiple carefully selected clinical and biological markers, using
both existing state-of-the-art technologies as well as pioneering, innovative approaches.
The study is designed to identify moderators and mediators of treatment response for
depression in order to specify a biosignature of treatment response for depression.
Evaluation of the usefulness of these markers in a carefully conducted clinical trial
comparing an antidepressant to placebo will assist in developing a Depression Treatment
Response Index (DTRI) to help clinicians match treatments to patients with MDD, resulting in
timely selection of treatments best suited for individual patients and thus approaching
personalized treatment. The resulting index provides a truly novel means of synthesizing the
contribution of key clinical and biological parameters in an easy to use tool for clinical


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. To reduce biologic heterogeneity, we will only enroll
patients with early onset of DSM IV MDD (before age 30) because these criteria in probands
have been shown to be associated with increased familial loading in families. Patients will
also have recurrent MDD with 2 or more recurrences (including current episode).
Additionally, patients will be required to have a current symptom severity score of 14 or
more on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR), both at
study screening and at the randomization (baseline) visit. In the first stage, patients will
receive an 8−week course of treatment in one of the two study arms. As part of the
Sequential Multiple Assignment Randomized Trial (SMART) design patients that have not
achieved response at the end of 8 weeks to their stage one treatment, defined by < 50%
improvement on the Clinical Global Improvement scale (CGI), will be switched to Stage 2
treatment (8 weeks). Patients who have achieved satisfactory response (>= 50% improvement on
the CGI) will be continued on treatment for an additional 8 weeks.

Specific Aims

Moderator Aims (Aim 1): To identify baseline clinical, neuroimaging, neurophysiological, and
behavioral moderators of differential treatment outcome (mean symptom change and
tolerability) for sertraline (SERT, a serotonergic antidepressant) versus placebo (PBO) for
the treatment of MDD. Symptom change will be measured using mean change from baseline in the
17-item Hamilton Rating Scale for Depression (HRSD17). Tolerability will be measured using
the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) and the Treatment
Emergent Symptom Scale (TESS).

Mediator Aims (Aim 2): To identify early phase (week 1) changes in neuroimaging,
neurophysiological, and behavioral tasks as mediators of differential treatment outcomes
(symptom change, tolerability) to SERT and PBO.

Main Treatment Effects Aim (Aim 3): To compare the 8-week outcomes of SERT vs. PBO using
mixed model regression analysis to maximize power to discriminate treatment efficacy

Participant Eligibility

Inclusion Criteria:

- Adults, age 18-65

- Written informed consent obtained

- Outpatients with a current primary diagnosis of nonpsychotic recurrent or chronic MDD
per the SCID-I

- QIDS-SR score 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)

Exclusion Criteria:

- History of inadequate response (to trials at adequate dose for adequate duration) or
poor tolerability to sertraline (SERT) or bupropion (BUP)

- Pregnant or breastfeeding

- Plan to become pregnant over the ensuing 12 months following study entry or are
sexually active and not using adequate contraception

- History (lifetime) of psychotic depression, schizophrenia, bipolar (I, II, or NOS)
disorder, schizoaffective disorder, or other Axis I psychotic disorder

- Current primary anxiety disorder diagnosis

- Meeting DSM-IV criteria for substance abuse in the last 2 months or substance
dependence in the last 6 months (except for nicotine)

- Require immediate hospitalization for psychiatric disorder

- Have an unstable general medical condition (GMC) that will likely require
hospitalization or to be deemed terminal (life expectancy < 6 months after study

- Require medications for their GMCs that contraindicate any study medication

- Have epilepsy or other conditions requiring an anticonvulsant

- Receiving or have received during the index episode vagus nerve stimulation, ECT, or
rTMS, or other somatic antidepressant treatments

- Currently taking any of the following exclusionary medications: antipsychotic
medications, anticonvulsant medications, mood stabilizers, central nervous system
stimulants, daily use of benzodiazepines or hypnotics, or antidepressant medication
used for the treatment of depression or other purposes such as smoking cessation,
since these agents may interfere with the testing of the major hypotheses under
study. Nonexcluded concomitant medications are acceptable as long as their clinician
determines that antidepressant treatment is safe and appropriate.

- Significant liver disease that would contraindicate any study medication

- Taking thyroid medication for hypothyroidism may be included only if they have been
stable on the thyroid medication for 3 months

- Using agents that are potential augmenting agents (e.g., T3 in the absence of thyroid
disease, SAMe, St. John's Wort, lithium, buspirone, Omega 3 fatty acids)

- Therapy that is depression specific, such as CBT or Interpersonal Psychotherapy of
Depression (IPT) is not allowed during participation (participants can participate if
they are receiving psychotherapy that is not targeting the symptoms of depression,
such as supportive therapy, marital therapy).

- Subjects must be fluent in English and have the capacity to understand the nature of
the study and sign the written informed consent since non-English speaking personnel
are not available for this study, and the research instruments are not yet translated
and validated in other languages.

- Currently actively suicidal or considered a high suicide risk

- Are currently enrolled in another study, and participation in that study
contraindicates participation in the EMBARC study.

- Any reason not listed herein yet, determined by the site PI, medical personnel, or
designee that constitutes good clinical practice and that would in the opinion of the
site PI, medical personnel, or designee make participation in the study hazardous.