Effect of Intrinsic Patterns of Functional Brain Connectivity in Moderating Antidepressant Treatment Response in Major Depression
Publication: American Journal of Psychiatry
Abstract
Objective:
Major depressive disorder is associated with aberrant resting-state functional connectivity across multiple brain networks supporting emotion processing, executive function, and reward processing. The purpose of this study was to determine whether patterns of resting-state connectivity between brain regions predict differential outcome to antidepressant medication (sertraline) compared with placebo.
Methods:
Participants in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study underwent structural and resting-state functional MRI at baseline. Participants were then randomly assigned to receive either sertraline or placebo treatment for 8 weeks (N=279). A region of interest–based approach was utilized to compute functional connectivity between brain regions. Linear mixed-model intent-to-treat analyses were used to identify brain regions that moderated (i.e., differentially predicted) outcomes between the sertraline and placebo arms.
Results:
Prediction of response to sertraline involved several within- and between-network connectivity patterns. In general, higher connectivity within the default mode network predicted better outcomes specifically for sertraline, as did greater between-network connectivity of the default mode and executive control networks. In contrast, both placebo and sertraline outcomes were predicted (in opposite directions) by between-network hippocampal connectivity.
Conclusions:
This study identified specific functional network–based moderators of treatment outcome involving brain networks known to be affected by major depression. Specifically, functional connectivity patterns of brain regions between and within networks appear to play an important role in identifying a favorable response for a drug treatment for major depressive disorder.
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History
Received: 24 July 2018
Revision received: 9 January 2019
Revision received: 3 May 2019
Revision received: 26 June 2019
Accepted: 22 July 2019
Published online: 20 September 2019
Published in print: February 01, 2020
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Funding Information
National Institute of Mental Healthhttp://dx.doi.org/10.13039/100000025: U01MH092221, U01MH092250
Mr. Grannemann died in January 2019.Dr. Jha has received contract research support from Acadia Pharmaceuticals and Janssen Research. Dr. Greer has received research funding from NARSAD and contracted research support from Janssen Research and Development; she has received honoraria and/or consultant fees from Lundbeck and Takeda Pharmaceuticals International. Dr. Kurian has received grant support from Evotec, Forest Pharmaceuticals, Johnson & Johnson, Naurex, NIMH, Pfizer, Rexahn, and Targacept and is employed by Health Care Service Corporation. Dr. Fava has received research support from Abbot Laboratories Alkermes, American Cyanamid, Aspect Medical Systems, AstraZeneca, Avanir Pharmaceuticals, BioResearch, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clintara, Cerecor, Covance, Covidien, Eli Lilly, EnVivo Pharmaceuticals, Euthymics Bioscience, Forest Pharmaceuticals, Ganeden Biotech, GlaxoSmithKline, Harvard Clinical Research Institute, Hoffman-LaRoche, Icon Clinical Research, i3 Innovus/Ingenix, Janssen R&D, Jed Foundation, Johnson & Johnson Pharmaceutical Research and Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck, MedAvante, Methylation Sciences, NARSAD, National Center for Complementary and Alternative Medicine, Neuralstem, NIDA, NIMH, Novartis, Organon Pharmaceuticals, Pamlab, Pfizer, Pharmacia-Upjohn, Pharmaceutical Research Associates, Pharmavite, PharmoRx Therapeutics, Photothera, Reckitt Benckiser, Roche Pharmaceuticals, RCT Logic (formerly Clinical Trials Solutions), Sanofi-Aventis US, Shire, Solvay Pharmaceuticals, Stanley Medical Research Institute, Synthelabo, Tal Medical, and Wyeth-Ayerst Laboratories; he has served as adviser or consultant to Abbott Laboratories, Acadia, Affectis Pharmaceuticals, Alkermes, Amarin Pharma, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Avanir Pharmaceuticals, AXSOME Therapeutics, Bayer, Best Practice Project Management, Biogen, BioMarin Pharmaceuticals, Biovail Corporation, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, CNS Response, Compellis Pharmaceuticals, Cypress Pharmaceutical, DiagnoSearch Life Sciences, Dainippon Sumitomo Pharma, Dov Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly, EnVivo Pharmaceuticals, ePharmaSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, Forum Pharmaceuticals, GenOmind, GlaxoSmithKline, Grunenthal GmbH, i3 Innovus/Ingenis, Intracellular, Janssen Pharmaceutica, Jazz Pharmaceuticals, Johnson & Johnson Pharmaceutical Research and Development, Knoll Pharmaceuticals, Labopharm, Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, MSI Methylation Sciences, Naurex, Nestle Health Sciences, Neuralstem, Neuronetics, NextWave Pharmaceuticals, Novartis, Nutrition 21, Orexigen Therapeutics, Organon Pharmaceuticals, Osmotica, Otsuka Pharmaceuticals, Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals, Puretech Ventures, PsychoGenics, Psylin Neurosciences, RCT Logic (Formerly Clinical Trials Solutions), Rexahn Pharmaceuticals, Ridge Diagnostics, Roche, Sanofi-Aventis US, Sepracor, Servier Laboratories, Schering-Plough, Solvay Pharmaceuticals, Somaxon Pharmaceuticals, Somerset Pharmaceuticals, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Synthelabo, Taisho Pharmaceutical, Takeda Pharmaceutical Company, Tal Medical, Tetragenex Pharmaceuticals, TransForm Pharmaceuticals, Transcept Pharmaceuticals, Vanda Pharmaceuticals, and VistaGen; he has received speaking or publishing fees from Adamed, Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Cephalon, CME Institute/Physicians Postgraduate Press, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Imedex, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, Novartis, Organon Pharmaceuticals, Pfizer, PharmaStar, United BioSource, and Wyeth-Ayerst Laboratories; he has equity holdings in Compellis and PsyBrain; he has a patent for Sequential Parallel Comparison Design, which are licensed by Massachusetts General Hospital to Pharmaceutical Product Development, and a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by Massachusetts General Hospital to Biohaven; and he receives royalties for the MGH Cognitive and Physical Functioning Questionnaire, the Sexual Functioning Inventory, the Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs and Symptoms, the Symptoms of Depression Questionnaire, and SAFER, and from Lippincott, Williams & Wilkins, Wolkers Kluwer, and World Scientific Publishing. Dr. McGrath has received funding from the Forest Research Laboratories, Naurex Pharmaceuticals (now Allergan), the New York State Department of Mental Hygiene, NIMH, the Research Foundation for Mental Hygiene (New York State), and Sunovion Pharmaceuticals. Dr. McInnis has received research support from Janssen Pharmaceuticals; he has served as a consultant for Janssen Pharmaceuticals and Otsuka; and he is co-owner of Priori AI. Dr. Weissman has received funding from NARSAD, NIDA, NIMH, the Sackler Foundation, and the Templeton Foundation; and she receives royalties from American Psychiatric Association Press, MultiHealth Systems, Oxford University Press, and Perseus Press. Dr. Phillips has received funding from NIMH and an honorarium from Sunovion Pharmaceuticals. Dr. Etkin has received research funding from the Brain and Behavior Research Foundation, Brain Resource, Cohen Veterans Bioscience, Dana Foundation, the Department of Veterans Affairs, NIMH, and the Stanford Neurosciences Institute; he has served as a consultant for Acadia, Cervel, Janssen, Lundbeck, Otsuka, Posit Science, and Takeda; and he holds equity in Mindstrong Health and Akili Interactive. Dr. Trivedi has served as an adviser or consultant for Abbott Laboratories, Abdi Ibrahim, Akzo (Organon Pharmaceuticals), Alkermes, AstraZeneca, Axon Advisors, Bristol-Myers Squibb, Cephalon, Cerecor, CME Institute of Physicians, Concert Pharmaceuticals, Eli Lilly, Evotec, Fabre Kramer Pharmaceuticals, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Global Services, Janssen Pharmaceutica Products, Johnson & Johnson PRD, Libby, Lundbeck, Meade Johnson, MedAvante, Medtronic, Merck, Mitsubishi Tanabe Pharma Development America, Naurex, Neuronetics, Otsuka Pharmaceuticals, Pamlab, Parke-Davis Pharmaceuticals, Pfizer, PgxHealth, Phoenix Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Products, Sepracor, Shire Development, Sierra, SK Life and Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targacept, Transcept, VantagePoint, Vivus, and Wyeth-Ayerst Laboratories; he has received grants or research support from the Agency for Healthcare Research and Quality, Cyberonics, NARSAD, NIDA, and NIMH. The other authors report no financial relationships with commercial interests.Metrics & Citations
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