Abstract
Background: One in three clinical trial patients with major depressive disorder report symptomatic improvement with placebo. Strategies to mitigate the effect of placebo responses have focused on modifying study design with variable success. Identifying and excluding or controlling for individuals with a high likelihood of responding to placebo may improve clinical trial efficiency and avoid unnecessary medication trials. Methods: Participants included those assigned to the placebo arm (n = 141) of the Establishing Moderators and Biosignatures for Antidepressant Response in Clinical Care (EMBARC) trial. The elastic net was used to evaluate 283 baseline clinical, behavioral, imaging, and electrophysiological variables to identify the most robust yet parsimonious features that predicted depression severity at the end of the double-blind 8-week trial. Variables retained in at least 50% of the 100 imputed data sets were used in a Bayesian multiple linear regression model to simultaneously predict the probabilities of response and remission. Results: Lower baseline depression severity, younger age, absence of melancholic features or history of physical abuse, less anxious arousal, less anhedonia, less neuroticism, and higher average theta current density in the rostral anterior cingulate predicted a higher likelihood of improvement with placebo. The Bayesian model predicted remission and response with an actionable degree of accuracy (both AUC > 0.73). An interactive calculator was developed predicting the likelihood of placebo response at the individual level. Conclusion: Easy-to-measure clinical, behavioral, and electrophysiological assessments can be used to identify placebo responders with a high degree of accuracy. Development of this calculator based on these findings can be used to identify potential placebo responders.
Original language | English (US) |
---|---|
Pages (from-to) | 285-295 |
Number of pages | 11 |
Journal | Psychotherapy and Psychosomatics |
Volume | 87 |
Issue number | 5 |
DOIs | |
State | Published - Sep 1 2018 |
Keywords
- EMBARC trial
- Placebo responder
- Prediction index
ASJC Scopus subject areas
- Clinical Psychology
- Applied Psychology
- Psychiatry and Mental health
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A Novel Strategy to Identify Placebo Responders : Prediction Index of Clinical and Biological Markers in the EMBARC Trial. / Trivedi, Madhukar H.; South, Charles; Jha, Manish K.; Rush, A. John; Cao, Jing; Kurian, Benji; Phillips, Mary; Pizzagalli, Diego A.; Trombello, Joseph M.; Oquendo, Maria A.; Cooper, Crystal; Dillon, Daniel G.; Webb, Christian; Grannemann, Bruce D.; Bruder, Gerard; McGrath, Patrick J.; Parsey, Ramin; Weissman, Myrna; Fava, Maurizio.
In: Psychotherapy and Psychosomatics, Vol. 87, No. 5, 01.09.2018, p. 285-295.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A Novel Strategy to Identify Placebo Responders
T2 - Prediction Index of Clinical and Biological Markers in the EMBARC Trial
AU - Trivedi, Madhukar H.
AU - South, Charles
AU - Jha, Manish K.
AU - Rush, A. John
AU - Cao, Jing
AU - Kurian, Benji
AU - Phillips, Mary
AU - Pizzagalli, Diego A.
AU - Trombello, Joseph M.
AU - Oquendo, Maria A.
AU - Cooper, Crystal
AU - Dillon, Daniel G.
AU - Webb, Christian
AU - Grannemann, Bruce D.
AU - Bruder, Gerard
AU - McGrath, Patrick J.
AU - Parsey, Ramin
AU - Weissman, Myrna
AU - Fava, Maurizio
N1 - Funding Information: The EMBARC study was supported by the National Institute of Mental Health of the National Institutes of Health under award No. 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. Funding Information: Valeant Pharmaceuticals donated the Wellbutrin XL used in the study. This work was supported by the EMBARC National Co-ordinating Center at UT Southwestern Medical Center, Madhukar H. Trivedi, MD, Coordinating PI, and the Data Center at Columbia and Stony Brook Universities. We acknowledge Jennifer Fur-man, PhD, and Jeremy Kee, MA, for their administrative support. Funding Information: Dr. Pizzagalli: funding from NIMH and the Dana Foundation; consulting fees from BlackThorn Therapeutics, Boehringer Ingel-heim, Pfizer Inc., and Posit Science. Dr. Weissman: funding from NIMH, the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Sackler Foundation, and the Temple-ton Foundation; royalties from the Oxford University Press, Perseus Press, the American Psychiatric Association Press, and Multi-Health Systems. Dr. Trivedi has received consulting fees from or has served on the advisory boards of Alkeremes Inc., Akili Interactive, Navitor, and Otsuka America Pharmaceutical Inc.; he holds author agreements with Janssen Asia Pacific and Oxford University Press; honoraria from the American Psychiatric Association and grants from the Cancer Prevention and Research Institute of Texas (CPRIT), National Institute of Mental Health (NIMH), National Institute of Drug Abuse (NIDA), National Center for Advancing Translational Sciences (NCATS), Johnson & Johnson, and PCORI. Dr. Trombello currently owns stock in Merck and Gilead Sciences and within the past 36 months previously owned stock in Johnson & Johnson. Dr. Fava has received research support from Abbott Laboratories, Alkermes Inc., American Cyanamid, Aspect Medical Systems, AstraZeneca, Avanir Pharmaceuticals, BioResearch, BrainCells Inc., Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, Clintara LLC, Covance, Covidien, Eli Lilly and Company, EnVivo Pharmaceuticals Inc., Euthymics Bioscience Inc., Forest Pharmaceuticals Inc., Ganeden Biotech Inc., GlaxoS-mithKline, Harvard Clinical Research Institute, Hoffman-La-Roche, 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., NARSAD, National Center for Complementary and Alternative Medicine, Neuralstem Inc., NIDA, NIMH, Novartis AG, Organon Pharmaceuticals, PamLab LLC, Pfizer Inc., Pharmacia-Upjohn, Pharmaceutical Research Associates Inc., Pharmavite LLC, Phar-moRx 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, Synthelabo, Tal Medical, and Wyeth-Ayerst Laboratories; has served on the advisory board or consulted for 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 Bio-Pharma, 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., ePharmaSolu-tions, EPIX Pharmaceuticals Inc., Euthymics Bioscience Inc., Fab-re-Kramer Pharmaceuticals Inc., Forest Pharmaceuticals Inc., Forum Pharmaceuticals, GenOmind LLC, GlaxoSmithKline, Gru-nenthal GmbH, i3 Innovus/Ingenis, Intracellular, Janssen Pharma-ceutica, Jazz Pharmaceuticals Inc., Johnson & Johnson Pharmaceutical Research & Development LLC, Knoll Pharmaceuticals Corp., Labopharm Inc., Lorex Pharmaceuticals, Lundbeck Inc., Med-Avante Inc., Merck & Co. Inc., MSI Methylation Sciences Inc., Nau-rex 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., Pharmaceutical Product Development LLC, 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, Sano-fi-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 Ltd., Tal Medical Inc., Tetragenex Pharmaceuticals Inc., TransForm Pharmaceuticals Inc., Transcept Pharmaceuticals Inc., Vanda Pharmaceuticals Inc., and VistaGen Therapeutics; 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 Ingel-heim GmbH, Bristol-Myers Squibb, Cephalon Inc., CME Institute/ Physicians Postgraduate Press Inc., Eli Lilly and Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, Imedex LLC, Lippincott Williams & Wilkins, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, Novartis AG, Organon Pharmaceuticals, Pfizer Inc., PharmaStar, United BioSource Corp., Wolters Kluwer, World Scientific Publishing Co. Pte. Ltd., and Wyeth-Ayerst Laboratories; has equity holdings in Compellis and PsyBrain Inc.; holds patents for Sequential Parallel Comparison Design, licensed by MGH to Pharmaceutical Product Development LLC, and patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; holds copyrights for the MGH Cognitive & Physical Functioning Questionnaire, Sexual Functioning Inventory, Anti-depressant Treatment Response Questionnaire, Discontinuation-Emergent Signs & Symptoms, Symptoms of Depression Questionnaire, and SAFER. M.W. received funding from NIMH, NIDA, NARSAD, Sackler Foundation, and Templeton Foundation and receives royalties from Oxford University Press, Perseus Press, American Psychiatric Association Press, and MultiHealth Systems. M.H.T. is or has been an advisor/consultant and received fees from Abbott Laboratories Inc., Abdi Ibrahim, Akzo (Organon Pharmaceuticals Inc.), Alkermes, AstraZeneca, Axon Advisors, Bristol-Myers Squibb, Cephalon Inc., Cerecor, CME Institute of Physicians, Concert Pharmaceuticals Inc., Eli Lilly and Company, Evo-tec, Fabre Kramer Pharmaceuticals Inc., Forest Pharmaceuticals Inc., GlaxoSmithKline, Janssen Global Services LLC, Janssen Phar-maceutica Products LP, Johnson & Johnson Pharmaceutical Research & Development LLC, Libby, Lundbeck, Meade Johnson, MedAvante, Medtronic, Merck, Mitsubishi Tanabe Pharma Development America Inc., Naurex, Neuronetics, Otsuka Pharmaceuticals, Pamlab, Parke-Davis Pharmaceuticals Inc., Pfizer Inc., Pgx-Health, Phoenix Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Products Ltd., Sepracor, Shire Development Inc., Sierra, SK Life and Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targacept, Transcept, VantagePoint, Vivus, and Wyeth-Ayerst Laboratories and has received grants and/or research support from Agency for Healthcare Research and Quality, Cyberonics Inc., NARSAD, NIMH, and NIDA. Dr. Kurian has received research grant support from Targacept Inc., Pfizer Inc., Johnson & Johnson, Evotec, Rexahn, Naurex, Forest Pharmaceuticals Inc., and NIMH. Dr. McGrath has received research grant support from Forest Research Laboratories, Sunovion Pharmaceuticals, and Naurex. Dr. Oquendo receives royalties for use of the Columbia Suicide Severity Rating Scale. Her family owns stock in Bristol Myers Squibb. Dr. Rush has received consulting fees from Akili, Brain Resource Inc., Compass Inc., Curbstone Consultant LLC, Eli Lilly, Emmes Corp, Liva-Nova, Mind Linc., Sunovion, Takeda USA, and Taj Medical; speaking fees from Liva-Nova and Sing-Health; and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). He is also named co-inventor on two patents: US Patent No. 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS, and US Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events during Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. Drs. South, Jha, Cao, Phillips, Cooper, Dillon, Webb, Bruder, and Parsey, and Mr. Grannemann have no conflicts to report.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Background: One in three clinical trial patients with major depressive disorder report symptomatic improvement with placebo. Strategies to mitigate the effect of placebo responses have focused on modifying study design with variable success. Identifying and excluding or controlling for individuals with a high likelihood of responding to placebo may improve clinical trial efficiency and avoid unnecessary medication trials. Methods: Participants included those assigned to the placebo arm (n = 141) of the Establishing Moderators and Biosignatures for Antidepressant Response in Clinical Care (EMBARC) trial. The elastic net was used to evaluate 283 baseline clinical, behavioral, imaging, and electrophysiological variables to identify the most robust yet parsimonious features that predicted depression severity at the end of the double-blind 8-week trial. Variables retained in at least 50% of the 100 imputed data sets were used in a Bayesian multiple linear regression model to simultaneously predict the probabilities of response and remission. Results: Lower baseline depression severity, younger age, absence of melancholic features or history of physical abuse, less anxious arousal, less anhedonia, less neuroticism, and higher average theta current density in the rostral anterior cingulate predicted a higher likelihood of improvement with placebo. The Bayesian model predicted remission and response with an actionable degree of accuracy (both AUC > 0.73). An interactive calculator was developed predicting the likelihood of placebo response at the individual level. Conclusion: Easy-to-measure clinical, behavioral, and electrophysiological assessments can be used to identify placebo responders with a high degree of accuracy. Development of this calculator based on these findings can be used to identify potential placebo responders.
AB - Background: One in three clinical trial patients with major depressive disorder report symptomatic improvement with placebo. Strategies to mitigate the effect of placebo responses have focused on modifying study design with variable success. Identifying and excluding or controlling for individuals with a high likelihood of responding to placebo may improve clinical trial efficiency and avoid unnecessary medication trials. Methods: Participants included those assigned to the placebo arm (n = 141) of the Establishing Moderators and Biosignatures for Antidepressant Response in Clinical Care (EMBARC) trial. The elastic net was used to evaluate 283 baseline clinical, behavioral, imaging, and electrophysiological variables to identify the most robust yet parsimonious features that predicted depression severity at the end of the double-blind 8-week trial. Variables retained in at least 50% of the 100 imputed data sets were used in a Bayesian multiple linear regression model to simultaneously predict the probabilities of response and remission. Results: Lower baseline depression severity, younger age, absence of melancholic features or history of physical abuse, less anxious arousal, less anhedonia, less neuroticism, and higher average theta current density in the rostral anterior cingulate predicted a higher likelihood of improvement with placebo. The Bayesian model predicted remission and response with an actionable degree of accuracy (both AUC > 0.73). An interactive calculator was developed predicting the likelihood of placebo response at the individual level. Conclusion: Easy-to-measure clinical, behavioral, and electrophysiological assessments can be used to identify placebo responders with a high degree of accuracy. Development of this calculator based on these findings can be used to identify potential placebo responders.
KW - EMBARC trial
KW - Placebo responder
KW - Prediction index
UR - http://www.scopus.com/inward/record.url?scp=85052687658&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052687658&partnerID=8YFLogxK
U2 - 10.1159/000491093
DO - 10.1159/000491093
M3 - Article
C2 - 30110685
AN - SCOPUS:85052687658
VL - 87
SP - 285
EP - 295
JO - Psychotherapy and Psychosomatics
JF - Psychotherapy and Psychosomatics
SN - 0033-3190
IS - 5
ER -