Abstract
Objective:: To identify data-driven subgroups in Major Depressive Disorder (MDD) in order to elucidate underlying neural correlates and determine if these subgroups have utility in predicting response to antidepressant versus placebo. Methods:: Using 27 clinical measures at baseline of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, participants with MDD (n=244) were sub grouped using principal component (PC) analysis. Baseline-to-week-8 changes in depression severity with sertraline versus placebo were compared in these subgroups. Resting-state functional connectivity of these subgroups were compared to those of healthy controls (n=38). Results:: Eight subgroups were identified from four PCs: (PC1) severity of depression-associated symptoms, (PC2) sub-threshold mania and anhedonia, (PC3) childhood trauma, medical comorbidities, and sexual dysfunction, and (PC4) personality traits of openness and agreeableness. Participants with high childhood trauma experienced greater improvement with sertraline (Cohen's d=0.87), whereas those with either higher levels of subthreshold hypomanic symptoms (Cohen's d=0.67) or with lower levels of agreeableness and openness experienced greater improvement with placebo (Cohen's d=0.71). Participants with high childhood trauma had greater connectivity between salience and dorsal attention networks, whereas those with higher levels of subthreshold hypomanic symptoms and lower levels of agreeableness and openness had greater connectivity within limbic network and that of visual network with hippocampus and dorsal attention network. Conclusion:: Assessing history of childhood trauma, presence of subthreshold hypomanic symptoms and personality traits may help to identify subgroups of patients with MDD who respond differentially to sertraline or placebo and have distinct neural signatures.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 602-610 |
| Number of pages | 9 |
| Journal | Journal of affective disorders |
| Volume | 282 |
| DOIs | |
| State | Published - Mar 1 2021 |
Keywords
- Clinical
- Data Driven
- Major Depressive Disorder
- SSRI
- Subgroups
- fMRI
ASJC Scopus subject areas
- Clinical Psychology
- Psychiatry and Mental health
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Differential response to SSRI versus Placebo and distinct neural signatures among data-driven subgroups of patients with major depressive disorder. / Chin Fatt, Cherise R.; Cooper, Crystal M.; Jha, Manish K.; Minhajuddin, Abu; Rush, A. John; Trombello, Joseph M.; Fava, Maurizio; McInnis, Melvin; Weissman, Myrna; Trivedi, Madhukar H.
In: Journal of affective disorders, Vol. 282, 01.03.2021, p. 602-610.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Differential response to SSRI versus Placebo and distinct neural signatures among data-driven subgroups of patients with major depressive disorder
AU - Chin Fatt, Cherise R.
AU - Cooper, Crystal M.
AU - Jha, Manish K.
AU - Minhajuddin, Abu
AU - Rush, A. John
AU - Trombello, Joseph M.
AU - Fava, Maurizio
AU - McInnis, Melvin
AU - Weissman, Myrna
AU - Trivedi, Madhukar H.
N1 - Funding Information: Drs. Chin Fatt , and Cooper , have no disclosures or potential conflicts of interest. Dr. Jha has received contract research grants from Acadia Pharmaceuticals and Janssen Research & Development, and honoraria for CME presentations from North American Center for Continuing Medical Education and Global Medical Education. Dr. A. J. Rush has received consulting fees from Akili, Brain Resource Inc., Compass Inc., Curbstone Consultant LLC, Emmes Corp., Holmusk, Johnson and Johnson (Janssen), Liva-Nova, Mind Linc, Otsuka-US, Sunovion; speaking fees from Liva-Nova, Otsuka-US; 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: U.S. 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 U.S. 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. Dr. Trombello currently owns stock in Merck and Gilead Sciences. Dr. Kurian has received grant support from Targacept, Inc., Pfizer, Inc., Johnson & Johnson, Evotec, Rexahn, Naurex, Forest Pharmaceuticals, and NIMH. Dr. Fava has received research support from Abbott Laboratories; Acadia Pharmaceuticals; Alkermes, Inc.; American Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; AXSOME Therapeutics; BioClinica, Inc; Biohaven; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Cerecor; Clarus Funds; Clexio Biosciences; Clintara, LLC; Covance; Covidien; Eli Lilly and Company;EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; FORUM Pharmaceuticals; Ganeden Biotech, Inc.; Gentelon, LLC; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; Indivior; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; Marinus Pharmaceuticals; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Coordinating Center for Integrated Medicine (NiiCM); National Institute of Drug Abuse (NIDA); National Institutes of Health; National Institute of Mental Health (NIMH); Neuralstem, Inc.; NeuroRx; Novartis AG; Organon Pharmaceuticals; Otsuka Pharmaceutical Development, Inc.; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC; PharmoRx Therapeutics; Photothera; Premiere Research International; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shenox Pharmaceuticals, LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Taisho Pharmaceuticals; Takeda Pharmaceuticals; Tal Medical; VistaGen; Wyeth-Ayerst Laboratories. He has served as advisor or consultant to bbott Laboratories; Acadia; Affectis Pharmaceuticals AG; Alfasigma USA, Inc.; Alkermes, Inc.; Amarin Pharma Inc.; Amorsa Therapeutics, Inc.; Aptinyx Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; Biogen; BioMarin Pharmaceuticals, Inc.; BioXcel Therapeutics; Biovail Corporation; Boehringer Ingelheim; Boston Pharmaceuticals; BrainCells Inc; Bristol-Myers Squibb; Cambridge Science Corporation; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; Clexio Biosciences; Click Therapeutics, Inc; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dainippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; ElMindA; EnVivo Pharmaceuticals, Inc.; Enzymotec LTD; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Esthismos Research, Inc.; Euthymics Bioscience, Inc.; Evecxia Therapeutics, Inc.; ExpertConnect, LLC; FAAH Research Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; Gate Neurosciences, Inc.; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; Happify; H. Lundbeck A/S; Indivior; i3 Innovus/Ingenis; Intracellular; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; JDS Therapeutics, LLC; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; Marinus Pharmaceuticals; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Navitor Pharmaceuticals, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neurocrine Biosciences, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Niraxx Light Therapeutics, Inc; Northwestern University; Novartis AG; Nutrition 21; Opiant Pharmecuticals; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Osmotica; Otsuka Pharmaceuticals; Ovid Therapeutics, Inc.; Pamlab, LLC.; Perception Neuroscience; Pfizer Inc.; PharmaStar; Pharmavite® LLC.; PharmoRx Therapeutics; Polaris Partners; Praxis Precision Medicines; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PPD; PThera, LLC; Purdue Pharma; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Relmada Therapeutics, Inc.; Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sentier Therapeutics; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Shenox Pharmaceuticals, LLC; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sonde Health; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Taisho Pharmaceuticals; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex; Teva Pharmaceuticals; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Usona Institute,Inc.; Vanda Pharmaceuticals, Inc.; Versant Venture Management, LLC; VistaGen. He has equity holdings in Compellis and PsyBrain, Inc.; he has a patent for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691). 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). In the past two years, Dr. Melvin McInnis has no conflicts of interest with respect to this paper. 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. Dr. Phillips received funding from the National Institute of Mental Health (NIMH). Dr. 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 Pharmaceutical 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 the National Institute on Drug Abuse. 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 corresponding author had full access to all study data and had final responsibility for the decision to submit the paper for publication. This work was also funded in part by the Hersh Foundation (Trivedi MH PI). We appreciate the editorial support of Jon Kilner, MS, MA (Pittsburgh), who was funded by the Center for Depression Research and Clinical Care (Trivedi MH PI).
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Objective:: To identify data-driven subgroups in Major Depressive Disorder (MDD) in order to elucidate underlying neural correlates and determine if these subgroups have utility in predicting response to antidepressant versus placebo. Methods:: Using 27 clinical measures at baseline of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, participants with MDD (n=244) were sub grouped using principal component (PC) analysis. Baseline-to-week-8 changes in depression severity with sertraline versus placebo were compared in these subgroups. Resting-state functional connectivity of these subgroups were compared to those of healthy controls (n=38). Results:: Eight subgroups were identified from four PCs: (PC1) severity of depression-associated symptoms, (PC2) sub-threshold mania and anhedonia, (PC3) childhood trauma, medical comorbidities, and sexual dysfunction, and (PC4) personality traits of openness and agreeableness. Participants with high childhood trauma experienced greater improvement with sertraline (Cohen's d=0.87), whereas those with either higher levels of subthreshold hypomanic symptoms (Cohen's d=0.67) or with lower levels of agreeableness and openness experienced greater improvement with placebo (Cohen's d=0.71). Participants with high childhood trauma had greater connectivity between salience and dorsal attention networks, whereas those with higher levels of subthreshold hypomanic symptoms and lower levels of agreeableness and openness had greater connectivity within limbic network and that of visual network with hippocampus and dorsal attention network. Conclusion:: Assessing history of childhood trauma, presence of subthreshold hypomanic symptoms and personality traits may help to identify subgroups of patients with MDD who respond differentially to sertraline or placebo and have distinct neural signatures.
AB - Objective:: To identify data-driven subgroups in Major Depressive Disorder (MDD) in order to elucidate underlying neural correlates and determine if these subgroups have utility in predicting response to antidepressant versus placebo. Methods:: Using 27 clinical measures at baseline of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, participants with MDD (n=244) were sub grouped using principal component (PC) analysis. Baseline-to-week-8 changes in depression severity with sertraline versus placebo were compared in these subgroups. Resting-state functional connectivity of these subgroups were compared to those of healthy controls (n=38). Results:: Eight subgroups were identified from four PCs: (PC1) severity of depression-associated symptoms, (PC2) sub-threshold mania and anhedonia, (PC3) childhood trauma, medical comorbidities, and sexual dysfunction, and (PC4) personality traits of openness and agreeableness. Participants with high childhood trauma experienced greater improvement with sertraline (Cohen's d=0.87), whereas those with either higher levels of subthreshold hypomanic symptoms (Cohen's d=0.67) or with lower levels of agreeableness and openness experienced greater improvement with placebo (Cohen's d=0.71). Participants with high childhood trauma had greater connectivity between salience and dorsal attention networks, whereas those with higher levels of subthreshold hypomanic symptoms and lower levels of agreeableness and openness had greater connectivity within limbic network and that of visual network with hippocampus and dorsal attention network. Conclusion:: Assessing history of childhood trauma, presence of subthreshold hypomanic symptoms and personality traits may help to identify subgroups of patients with MDD who respond differentially to sertraline or placebo and have distinct neural signatures.
KW - Clinical
KW - Data Driven
KW - Major Depressive Disorder
KW - SSRI
KW - Subgroups
KW - fMRI
UR - http://www.scopus.com/inward/record.url?scp=85099207327&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099207327&partnerID=8YFLogxK
U2 - 10.1016/j.jad.2020.12.102
DO - 10.1016/j.jad.2020.12.102
M3 - Article
C2 - 33445082
AN - SCOPUS:85099207327
VL - 282
SP - 602
EP - 610
JO - Journal of Affective Disorders
JF - Journal of Affective Disorders
SN - 0165-0327
ER -