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

Depression Clinical Trial

— EMBARC  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01407094
• Other study ID #: STU 092010-151
• Status: Completed
• Phase: Phase 2
• Start date: July 29, 2011
• Est. completion date: April 2016

Study information

• Verified date: December 2018
• Source: University of Texas Southwestern Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 296
• Est. completion date: April 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

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 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.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder

Intervention

Drug:
• Sertraline
50-200mg/day
• Placebo
1-4 pills per day
• BupropionXL
150-450 mg/day

Locations

Country	Name	City	State
United States	University of Michigan Ann Arbor	Ann Arbor	Michigan
United States	Massachusetts General Hospital Boston	Boston	Massachusetts
United States	UT Southwestern Medical Center Dallas	Dallas	Texas
United States	Columbia Univerisity New York City	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
University of Texas Southwestern Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (10)

Chase HW, Fournier JC, Greenberg T, Almeida JR, Stiffler R, Zevallos CR, Aslam H, Cooper C, Deckersbach T, Weyandt S, Adams P, Toups M, Carmody T, Oquendo MA, Peltier S, Fava M, McGrath PJ, Weissman M, Parsey R, McInnis MG, Kurian B, Trivedi MH, Phillips ML. Accounting for Dynamic Fluctuations across Time when Examining fMRI Test-Retest Reliability: Analysis of a Reward Paradigm in the EMBARC Study. PLoS One. 2015 May 11;10(5):e0126326. doi: 10.1371/journal.pone.0126326. eCollection 2015. — View Citation

Fournier JC, Chase HW, Greenberg T, Etkin A, Almeida JR, Stiffler R, Deckersbach T, Weyandt S, Cooper C, Toups M, Carmody T, Kurian B, Peltier S, Adams P, McInnis MG, Oquendo MA, McGrath PJ, Fava M, Weissman M, Parsey R, Trivedi MH, Phillips ML. Neuroticism and Individual Differences in Neural Function in Unmedicated Major Depression: Findings from the EMBARC Study. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Mar;2(2):138-148. doi: 10.1016/j.bpsc.2016.11.008. Epub 2016 Dec 6. — View Citation

Greenberg T, Chase HW, Almeida JR, Stiffler R, Zevallos CR, Aslam HA, Deckersbach T, Weyandt S, Cooper C, Toups M, Carmody T, Kurian B, Peltier S, Adams P, McInnis MG, Oquendo MA, McGrath PJ, Fava M, Weissman M, Parsey R, Trivedi MH, Phillips ML. Moderation of the Relationship Between Reward Expectancy and Prediction Error-Related Ventral Striatal Reactivity by Anhedonia in Unmedicated Major Depressive Disorder: Findings From the EMBARC Study. Am J Psychiatry. 2015 Sep 1;172(9):881-91. doi: 10.1176/appi.ajp.2015.14050594. Epub 2015 Jul 17. — View Citation

Petkova E, Ogden RT, Tarpey T, Ciarleglio A, Jiang B, Su Z, Carmody T, Adams P, Kraemer HC, Grannemann BD, Oquendo MA, Parsey R, Weissman M, McGrath PJ, Fava M, Trivedi MH. Statistical Analysis Plan for Stage 1 EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) Study. Contemp Clin Trials Commun. 2017 Jun;6:22-30. doi: 10.1016/j.conctc.2017.02.007. Epub 2017 Feb 24. — View Citation

Pizzagalli DA, Webb CA, Dillon DG, Tenke CE, Kayser J, Goer F, Fava M, McGrath P, Weissman M, Parsey R, Adams P, Trombello J, Cooper C, Deldin P, Oquendo MA, McInnis MG, Carmody T, Bruder G, Trivedi MH. Pretreatment Rostral Anterior Cingulate Cortex Theta Activity in Relation to Symptom Improvement in Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Jun 1;75(6):547-554. doi: 10.1001/jamapsychiatry.2018.0252. — View Citation

Trivedi MH, McGrath PJ, Fava M, Parsey RV, Kurian BT, Phillips ML, Oquendo MA, Bruder G, Pizzagalli D, Toups M, Cooper C, Adams P, Weyandt S, Morris DW, Grannemann BD, Ogden RT, Buckner R, McInnis M, Kraemer HC, Petkova E, Carmody TJ, Weissman MM. Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC): Rationale and design. J Psychiatr Res. 2016 Jul;78:11-23. doi: 10.1016/j.jpsychires.2016.03.001. Epub 2016 Mar 15. — View Citation

Trivedi MH, South C, Jha MK, Rush AJ, Cao J, Kurian B, Phillips M, Pizzagalli DA, Trombello JM, Oquendo MA, Cooper C, Dillon DG, Webb C, Grannemann BD, Bruder G, McGrath PJ, Parsey R, Weissman M, Fava M. A Novel Strategy to Identify Placebo Responders: Prediction Index of Clinical and Biological Markers in the EMBARC Trial. Psychother Psychosom. 2018;87(5):285-295. doi: 10.1159/000491093. Epub 2018 Aug 15. — View Citation

Trombello JM, Pizzagalli DA, Weissman MM, Grannemann BD, Cooper CM, Greer TL, Malchow AL, Jha MK, Carmody TJ, Kurian BT, Webb CA, Dillon DG, McGrath PJ, Bruder G, Fava M, Parsey RV, McInnis MG, Adams P, Trivedi MH. Characterizing anxiety subtypes and the relationship to behavioral phenotyping in major depression: Results from the EMBARC study. J Psychiatr Res. 2018 Jul;102:207-215. doi: 10.1016/j.jpsychires.2018.04.003. Epub 2018 Apr 6. — View Citation

Ulke C, Tenke CE, Kayser J, Sander C, Böttger D, Wong LYX, Alvarenga JE, Fava M, McGrath PJ, Deldin PJ, Mcinnis MG, Trivedi MH, Weissman MM, Pizzagalli DA, Hegerl U, Bruder GE. Resting EEG Measures of Brain Arousal in a Multisite Study of Major Depression. Clin EEG Neurosci. 2018 Sep 5:1550059418795578. doi: 10.1177/1550059418795578. [Epub ahead of print] — View Citation

Webb CA, Trivedi MH, Cohen ZD, Dillon DG, Fournier JC, Goer F, Fava M, McGrath PJ, Weissman M, Parsey R, Adams P, Trombello JM, Cooper C, Deldin P, Oquendo MA, McInnis MG, Huys Q, Bruder G, Kurian BT, Jha M, DeRubeis RJ, Pizzagalli DA. Personalized prediction of antidepressant v. placebo response: evidence from the EMBARC study. Psychol Med. 2018 Jul 2:1-10. doi: 10.1017/S0033291718001708. [Epub ahead of print] — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hamilton Rating Scale for Depression	The Hamilton Rating Scale for depression is a measure of depressive severity (HAM-D17; HDRS); Scores range from 0-52; Lower scores indicate less depressive symptomatology, and so are the more desirable.	Week 8

External Links

•   EMBARC Study Website