Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 11-23 |
| Number of pages | 13 |
| Journal | Journal of Psychiatric Research |
| Volume | 78 |
| DOIs | |
| State | Published - Jul 1 2016 |
Keywords
- Antidepressant response
- Biosignatures
- EMBARC
- Mediators
- Moderators
- Sertraline
ASJC Scopus subject areas
- Psychiatry and Mental health
- Biological Psychiatry
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Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) : Rationale and design. / Trivedi, Madhukar H.; McGrath, Patrick J.; Fava, Maurizio et al.
In: Journal of Psychiatric Research, Vol. 78, 01.07.2016, p. 11-23.Research output: Contribution to journal › Review article › peer-review
}
TY - JOUR
T1 - Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC)
T2 - Rationale and design
AU - Trivedi, Madhukar H.
AU - McGrath, Patrick J.
AU - Fava, Maurizio
AU - Parsey, Ramin V.
AU - Kurian, Benji T.
AU - Phillips, Mary L.
AU - Oquendo, Maria A.
AU - Bruder, Gerard
AU - Pizzagalli, Diego
AU - Toups, Marisa
AU - Cooper, Crystal
AU - Adams, Phil
AU - Weyandt, Sarah
AU - Morris, David W.
AU - Grannemann, Bruce D.
AU - Ogden, R. Todd
AU - Buckner, Randy
AU - McInnis, Melvin
AU - Kraemer, Helena C.
AU - Petkova, Eva
AU - Carmody, Thomas J.
AU - Weissman, Myrna M.
N1 - Funding Information: The EMBARC study was supported by the National Institute of Mental Health of the National Institutes of Health under award numbers U01MH092221 (Trivedi, M.H.) and U01MH092250 (McGrath, P.J., Parsey, R.V., Weissman, M.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Valeant Pharmaceuticals donated the Wellbutrin XL used in the study. This work was supported by the EMBARC National Coordinating Center at UT Southwestern Medical Center, Madhukar H. Trivedi, M.D., Coordinating PI, and the Data Center at Columbia and Stony Brook Universities. Funding Information: Dr. Madhukar H. Trivedi, is or has been an advisor/consultant and received fee from (lifetime disclosure): Abbott Laboratories, Inc., Abdi Ibrahim, Akzo (Organon Pharmaceuticals Inc.), Alkermes, AstraZeneca, Axon Advisors, Bristol-Myers Squibb Company, Cephalon, Inc., Cerecor, CME Institute of Physicians, Concert Pharmaceuticals, Inc., Eli Lilly & Company, Evotec, Fabre Kramer Pharmaceuticals, Inc., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Global Services, LLC, Janssen Pharmaceutica Products, LP, Johnson & Johnson PRD, Libby, Lundbeck, Meade Johnson, MedAvante, Medtronic, Merck, Mitsubishi Tanabe Pharma Development America, Inc., Naurex, Neuronetics, Otsuka Pharmaceuticals, Pamlab, Parke-Davis Pharmaceuticals, Inc., Pfizer Inc., PgxHealth, Phoenix Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Products Ltd., Sepracor, SHIRE Development, Sierra, SK Life and Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targacept, Transcept, VantagePoint, Vivus, and Wyeth-Ayerst Laboratories. In addition, he has received grants/research support from: Agency for Healthcare Research and Quality (AHRQ), Cyberonics, Inc., National Alliance for Research in Schizophrenia and Depression, National Institute of Mental Health and National Institute on Drug Abuse. Dr. Thilo Deckersbach's research has been funded by NIH, NIMH, NARSAD, TSA, IOCDF, Tufts University, DBDAT and Otsuka Pharmaceuticals, he has received honoraria, consultation fees and/or royalties from the MGH Psychiatry Academy, BrainCells Inc., Clintara, LLC, Inc., Systems Research and Applications Corporation, Boston University, the Catalan Agency for Health Technology Assessment and Research, the National Association of Social Workers Massachusetts, the Massachusetts Medical Society, Tufts University, NIDA, NIMH, Oxford University Press, Guilford Press, and Rutledge. He has also participated in research funded by DARPA, NIH, NIA, AHRQ, PCORI, Janssen Pharmaceuticals, The Forest Research Institute, Shire Development Inc., Medtronic, Cyberonics, Northstar, and Takeda. Dr. Pat McGrath has received funding from the National Institute of Mental Health, New York State Department of Mental Hygiene, Research Foundation for Mental Hygiene (New York State), Forest Research Laboratories, Sunovion Pharmaceuticals, and Naurex Pharmaceuticals (now Allergan). Dr. Fava has received research support from Abbot Laboratories; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Cerecor; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc.; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC; PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Tal Medical; Wyeth-Ayerst Laboratories; he has served as advisor or consultant to Abbott Laboratories; Acadia; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; Biogen; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Intracellular; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Osmotica; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite® LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC Formerly Clinical Trials Solutions, LLC; Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Taisho Pharmaceutical; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc.; VistaGen; he has received speaking or publishing fees from Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource, Corp.; Wyeth-Ayerst Laboratories; he has equity holdings in Compellis and PsyBrain, Inc.; he has a patent for Sequential Parallel Comparison Design (SPCD), which are licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven; and he receives copyright royalties for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd. Funding Information: This study was supported in part by Valeant Pharmaceuticals who donated the Wellbutrin XL used in this study. We would also like to thank the EMBARC National Coordinating Center at UT Southwestern Medical Center, Madhukar H. Trivedi, M.D., Coordinating PI, and the Data Center at Columbia University. We also thank Carol A. Tamminga, M.D., Communities Foundation of Texas, Inc. Chair in Brain Science, and Chair, Department of Psychiatry, University of Texas Southwestern Medical Center for administrative support and Cassandra Hatt for assistance with manuscript preparation and submission. Funding Information: Dr. Ramin Parsey reports no relevant or material financial interests that relate to the research described in this paper. Dr. Benji Kurian has received research grant support from the following organizations: Targacept, Inc., Pfizer, Inc., Johnson & Johnson, Evotec, Rexahn, Naurex, Forest Pharmaceuticals and the National Institute of Mental Health (NIMH). Mary L. Phillips has received funding from NIMH and the Emmerling-Pittsburgh Foundation. Dr. Oquendo receives royalties for use of the Columbia Suicide Severity Rating Scale and received financial compensation from Pfizer for the safety evaluation of a clinical facility, unrelated to this study. She is the recipient of a grant from Eli Lilly to support a year's salary for the Lilly Suicide Scholar, Enrique Baca-Garcia, M.D., Ph.D.; she has received unrestricted educational grants and/or lecture fees from Astra-Zeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Otsuko, Pfizer, Sanofi-Aventis, and Shire. Her family owns stock in Bristol Myers Squibb. Gerard Bruder have no conflicts of interest with respect to this paper. Over the past three years, Dr. Pizzagalli has received honoraria/consulting fees from Advanced Neurotechnology North America, AstraZeneca, Otsuka America Pharmaceutical, Pfizer, and Servier for activities unrelated to this project. Dr. Marisa Toups has received travel funds from Janssen Research and Development and currently receives compensation for serving on a data safety and monitoring board for Otsuka Pharmaceuticals. Dr. Crystal Cooper, Dr. Phil Adams, and Dr. Sarah Weyandt report no competing interests. Drs. Morris and Grannemann do have any conflicting interests to report. Dr. Todd Ogden reports no conflicting interests. Dr. Randy Buckner is a paid consultant for Pfizer, Inc. Dr. Melvin McInnis has no conflicts of interest with respect to this paper. Dr. Helena C. Kraemer does not have any conflicts. Dr. Eva Petkova reports no conflicting interests. Dr. Thomas Carmody does not report any conflicting interests. In the past two years, Dr. Myrna Weissman received funding from the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Sackler Foundation, the Templeton Foundation; and receives royalties from the Oxford University Press, Perseus Press, the American Psychiatric Association Press, and MultiHealth Systems. Publisher Copyright: © 2016 Elsevier Ltd.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - Antidepressant response
KW - Biosignatures
KW - EMBARC
KW - Mediators
KW - Moderators
KW - Sertraline
UR - http://www.scopus.com/inward/record.url?scp=84962220007&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84962220007&partnerID=8YFLogxK
U2 - 10.1016/j.jpsychires.2016.03.001
DO - 10.1016/j.jpsychires.2016.03.001
M3 - Review article
C2 - 27038550
AN - SCOPUS:84962220007
SN - 0022-3956
VL - 78
SP - 11
EP - 23
JO - Journal of Psychiatric Research
JF - Journal of Psychiatric Research
ER -