Clinical trial NCT01407094: Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression
Official title: Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) for Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Depression
Keywords: Depression, Major Depressive Disorder, Mood Disorder
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
First posted: 2011-08-01
Enrollment: 296
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Patients were entered into Stage 1, treated with sertraline (Treatment A) or placebo (Treatment B), and used for the primary analysis which included the identification of potential mediators and moderators of response for these two treatments.

In stage two, responders to Treatment A remained on sertraline, and non-responders were switched to bupropion (Treatment C). Responders to Treatment B remained on placebo, and non-responders were switched to sertraline (Treatment D).
Primary purpose: OTHER

Brief summary: 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 care.

Detailed description: 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 a 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 the 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 differences.

Primary Outcomes:

- 17-item Hamilton Rating Scale for Depression (HRSD17)

Secondary Outcomes:

- the Frequency, Intensity, and Burden Side Effects Rating (FIBSER)

Eligibility criteria: 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 entry)
* 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.

Primary outcomes:
measure: Hamilton Rating Scale for Depression
timeFrame: Week 8
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Ann Arbor
state: Michigan
city: New York
country: United States
facility: Columbia Univerisity New York City
state: New York
city: Dallas
country: United States
facility: UT Southwestern Medical Center Dallas
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Madhukar H Trivedi, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: Patrick J McGrath, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: Myrna Weissman, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: Ramin Parsey, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Maurizio Fava, M.D.
role: PRINCIPAL_INVESTIGATOR
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